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1
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Zhang Y, Desai N, Connolly D. The Use of Apabetalone in Reducing Cardiovascular Outcomes, Based on the Current Evidence and Trials. Eur Cardiol 2025; 20:e04. [PMID: 40134629 PMCID: PMC11934121 DOI: 10.15420/ecr.2023.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 06/18/2024] [Indexed: 03/27/2025] Open
Abstract
The use of apabetalone, a novel therapeutic agent targeting epigenetic regulation, has been the source of much interest in its ability to subvert major adverse cardiovascular events. Derived from BETonMACE, clinical trials have explored its potential benefits in improving cardiovascular health. Apabetalone operates through selective inhibition of bromodomain and extra-terminal domain proteins, influencing gene expression and cellular pathways implicated in cardiovascular disease progression to influence lipid metabolism, downplay oxidative burden and reduce inflammation. The BETonMACE trial recruited patients with type 2 diabetes and recent acute coronary syndrome events. The primary endpoint was the composite of cardiovascular death, MI and stroke. This article explores the various clinical research and outcomes related to apabetalone and its use in the context of its proposed mechanism.
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Affiliation(s)
- Yimeng Zhang
- Department of Cardiology, Sandwell and West Birmingham Trust West Midlands, UK
| | - Nimai Desai
- Department of Cardiology, Sandwell and West Birmingham Trust West Midlands, UK
| | - Derek Connolly
- Department of Cardiology, Sandwell and West Birmingham Trust West Midlands, UK
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2
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Ran K, Li Y, Zhang YM, Tang DY, Chen ZZ, Xu ZG, Zhang L, Wang BC, Huang JH. Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy. Bioorg Chem 2024; 153:107929. [PMID: 39509789 DOI: 10.1016/j.bioorg.2024.107929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/15/2024] [Accepted: 10/27/2024] [Indexed: 11/15/2024]
Abstract
The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC50 values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC50 value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of cancer therapy.
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Affiliation(s)
- Kai Ran
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China; Chongqing Academy of Chinese Materia Medica, No. 34 Nanshan Road, Nan'an District, Chongqing 400065, China; Key Laboratory of Bio-theological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
| | - Yong Li
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Yi-Mei Zhang
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Dian-Yong Tang
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Zhong-Zhu Chen
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Zhi-Gang Xu
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Li Zhang
- Chongqing Academy of Chinese Materia Medica, No. 34 Nanshan Road, Nan'an District, Chongqing 400065, China
| | - Bo-Chu Wang
- Key Laboratory of Bio-theological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Jiu-Hong Huang
- College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China.
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Dai W, Qiao X, Fang Y, Guo R, Bai P, Liu S, Li T, Jiang Y, Wei S, Na Z, Xiao X, Li D. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Transduct Target Ther 2024; 9:332. [PMID: 39592582 PMCID: PMC11627502 DOI: 10.1038/s41392-024-02039-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.
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Affiliation(s)
- Wanlin Dai
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinbo Qiao
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuanyuan Fang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Renhao Guo
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Bai
- Department of Forensic Genetics, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Shuang Liu
- Shenyang Maternity and Child Health Hospital, Shenyang, China
| | - Tingting Li
- Department of General Internal Medicine VIP Ward, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yutao Jiang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuang Wei
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhijing Na
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
| | - Xue Xiao
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China.
| | - Da Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang, China.
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Sun M, Clayton N, Alam S, Asmussen N, Wong A, Kim JH, Luong G, Mokhtari S, Pellei D, Carrico CK, Schwartz Z, Boyan BD, Giannobile WV, Sahingur SE, Lin Z. Selective BET inhibitor RVX-208 ameliorates periodontal inflammation and bone loss. J Clin Periodontol 2023; 50:1658-1669. [PMID: 37855275 DOI: 10.1111/jcpe.13887] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 09/06/2023] [Accepted: 09/20/2023] [Indexed: 10/20/2023]
Abstract
AIM To determine the effects of RVX-208, a selective bromodomain and extra-terminal domain (BET) inhibitor targeting bromodomain 2 (BD2), on periodontal inflammation and bone loss. MATERIALS AND METHODS Macrophage-like cells (RAW264.7) and human gingival epithelial cells were challenged by Porphyromonas gingivalis (Pg) with or without RVX-208. Inflammatory gene expression and cytokine production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RAW264.7 cells were induced to osteoclast differentiation. After RVX-208 treatment, osteoclast differentiation was evaluated by histology, tartrate-resistant-acid-phosphatase (TRAP) activity and the expression of osteoclast-specific genes. The effect of RVX-208 on osteoclast transcriptome was studied by RNA sequencing. Periodontitis was induced in rats by ligature and local RVX-208 treatment was administered every other day. Alveolar bone loss was measured by micro-computed tomography. RESULTS RVX-208 inhibited inflammatory gene expression and cytokine production in Pg-infected cells. Osteoclast differentiation was inhibited by RVX-208, as evidenced by reduced osteoclast number, TRAP activity and osteoclast-specific gene expression. RVX-208 displayed a more selective and less profound suppressive impact on transcriptome compared with pan-BET inhibitor, JQ1. RVX-208 administration prevented the alveolar bone loss in vivo. CONCLUSIONS RVX-208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi-drug' for the prevention of periodontitis.
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Affiliation(s)
- Mingxu Sun
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
- Jianbo Dental Clinic, Qingdao, People's Republic of China
| | - Nicholas Clayton
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Sheikh Alam
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Niels Asmussen
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Andrew Wong
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jin Ha Kim
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Gary Luong
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Sasan Mokhtari
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - David Pellei
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Caroline K Carrico
- Department of Dental Public Health and Policy, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Zvi Schwartz
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Barbara D Boyan
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, USA
| | - William V Giannobile
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Sinem Esra Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Zhao Lin
- Department of Periodontics, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA
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Parente M, Tonini C, Segatto M, Pallottini V. Regulation of cholesterol metabolism: New players for an old physiological process. J Cell Biochem 2023; 124:1449-1465. [PMID: 37796135 DOI: 10.1002/jcb.30477] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 10/06/2023]
Abstract
Identified more than two centuries ago, cholesterol plays a pivotal role in human physiology. Since cholesterol metabolism is a physiologically significant process, it is not surprising that its alterations are associated with several pathologies. The discovery of new molecular targets or compounds able to modulate this sophisticated metabolism has been capturing the attention of research groups worldwide since many years. Endogenous and exogenous compounds are known to regulate cellular cholesterol synthesis and uptake, or reduce cholesterol absorption at the intestinal level, thereby regulating cholesterol homeostasis. However, there is a great need of new modulators and diverse new pathways have been uncovered. Here, after illustrating cholesterol metabolism and its well-known regulators, some new players of this important physiological process are also described.
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Affiliation(s)
| | | | - Marco Segatto
- Department of Bioscience and Territory, University of Molise, Pesche, Italy
| | - Valentina Pallottini
- Department of Science, University Roma Tre, Rome, Italy
- Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano, Rome, Italy
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Chen C, Lu T, Chen P, Li Z, Yang Y, Fan S, Zhang Y, Chen K, Fu W, Wang Y, Luo C, Zhou B. Cyclization strategy leads to highly potent Bromodomain and extra-terminal (BET) Bromodomain inhibitors for the treatment of acute liver injury. Eur J Med Chem 2023; 247:115023. [PMID: 36566713 DOI: 10.1016/j.ejmech.2022.115023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/01/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response, and currently the main treatment for ALI is merely supportive rather than curative. Therefore, the development of novel and effective therapeutic strategies for ALI therapy is highly desirable. The emerging biological understanding of the role of BET Bromodomains has opened up an exciting opportunity to develop potent BET Bromodomain inhibitors as an effective therapeutic strategy for the treatment of acute liver injury. Herein, we synthesized a series of potent BET Bromodomain inhibitors with a tetracyclic scaffold, exemplified by compound 28 which showed good in vitro anti-inflammatory activity and good therapeutic effects in the LPS-induced acute liver injury model without obvious cytotoxicity, suggesting that compound 28 is a highly promising candidate worthy for further development.
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Affiliation(s)
- Chao Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tian Lu
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550025, China; Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Panyu Chen
- Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai, 200336, China
| | - Zizhou Li
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yaxi Yang
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shijie Fan
- Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuanyuan Zhang
- Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Kaixian Chen
- Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wei Fu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
| | - Yugang Wang
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai, 200336, China.
| | - Cheng Luo
- Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Bing Zhou
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases. Pharmaceuticals (Basel) 2022; 15:ph15081032. [PMID: 36015180 PMCID: PMC9414451 DOI: 10.3390/ph15081032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 11/16/2022] Open
Abstract
BET proteins, which recognize and bind to acetylated histones, play a key role in transcriptional regulation. The development of chemical BET inhibitors in 2010 greatly facilitated the study of these proteins. BETs play crucial roles in cancer, inflammation, heart failure, and fibrosis. In particular, BETs may be involved in regulating metabolic processes, such as adipogenesis and metaflammation, which are under tight transcriptional regulation. In addition, acetyl-CoA links energy metabolism with epigenetic modification through lysine acetylation, which creates docking sites for BET. Given this, it is possible that the ambient energy status may dictate metabolic gene transcription via a BET-dependent mechanism. Indeed, recent studies have reported that various BET proteins are involved in both metabolic signaling regulation and disease. Here, we discuss some of the most recent information on BET proteins and their regulation of the metabolism in both cellular and animal models. Further, we summarize data from some randomized clinical trials evaluating BET inhibitors for the treatment of metabolic diseases.
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Abstract
PURPOSE OF REVIEW Multiple studies have shown a strong association between lipids and diabetes. These are usually described through the effects of cholesterol content of lipid particles and in particular low-density lipoprotein. However, lipoprotein particles contain other components, such as phospholipids and more complex lipid species, such as ceramides and sphingolipids. Ceramides, such as sphingolipids are also produced intracellularly and have signalling actions in regulating cell metabolism including effects on inflammation, and potentially have a mechanistic role in the development of insulin resistance. RECENT FINDINGS Recently, techniques have been developed to analyse detailed molecular profiles of lipid particles - lipidomics. Proteomics has confirmed the different proteins associated with different particles but far less is known about the relationship of individual lipid species with diabetes and cardiovascular risk. A number of studies have now shown that the plasma lipidome, and in particular, ceramides and sphingolipids may predict the development of diabetes. SUMMARY Lipidomics had identified ceramides and sphingolipids as potential mediators of cellular dysfunction in diabetes. Further work is required to ascertain whether they have clinical utility.
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Affiliation(s)
- Eun Ji Kim
- Department of Metabolic Medicine/Chemical Pathology Guy's & St Thomas' Hospitals, London, UK
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Garrelfs SF, van Harskamp D, Peters-Sengers H, van den Akker CH, Wanders RJ, Wijburg FA, van Goudoever JB, Groothoff JW, Schierbeek H, Oosterveld MJ. Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients. J Am Soc Nephrol 2021; 32:3175-3186. [PMID: 34686543 PMCID: PMC8638398 DOI: 10.1681/asn.2021060729] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism, characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated, and upcoming therapies require more reliable outcome parameters than the currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo . METHODS Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1- 13 C]glycolate, [U- 13 C 2 ]oxalate, and, in a subgroup, [D 5 ]glycine. Isotopic enrichment of 13 C-labeled oxalate and glycolate were measured using a new gas chromatography-tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively. RESULTS Total daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, and controls, respectively ( P =0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1- 13 C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive. CONCLUSIONS This stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans.
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Affiliation(s)
- Sander F. Garrelfs
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Dewi van Harskamp
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Hessel Peters-Sengers
- Center for Experimental Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Ronald J.A. Wanders
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Frits A. Wijburg
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Jaap W. Groothoff
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Henk Schierbeek
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Michiel J.S. Oosterveld
- Emma’s Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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10
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Akawa OB, Soremekun OS, Olotu FA, Soliman MES. Atomistic insights into the selective therapeutic activity of 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a]pyrazin-1(2H)-one towards bromodomain-containing proteins. Comput Biol Chem 2021; 95:107592. [PMID: 34710811 DOI: 10.1016/j.compbiolchem.2021.107592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 09/29/2021] [Accepted: 10/12/2021] [Indexed: 10/20/2022]
Abstract
Cross-target effect has been one of the major mechanisms of drug toxicity, this has necessitated the design of inhibitors that are specifically tailored to target particular biomolecules. 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a] pyrazin-1(2H)-one (Cpd38) is an inhibitor possessing high inhibition rate and tailored specificity towards bromodomain-containing protein 4 (BRD4). In this research, we used an array of computational techniques to provide insight at the atomistic level the specific targeting of BRD4 by Cpd38 relative to the binding of Cpd38 with E1A binding protein P300 (EP300); another bromodomain-containing protein (BCP). Comparatively, binding of Cpd38 improved the conformational stability and compactness of BRD4 protein when compared to the Cpd38 bound EP300. Also, Cpd38 induced a conformational change in the active site of BRD4 that facilitated a complementary pose between Cpd38 and BRD4 suitable for effective atomistic interactions. Expectedly, thermodynamic calculations revealed that the Cpd38-BRD4 system had higher binding energy (-36.11 Kcal/mol) than the Cpd38-EP300 system with a free binding energy of -15.86 Kcal/mol. Noteworthy is the opposing role Trp81 (acting as hydrogen bond acceptor) and Pro1074 (acting as hydrogen bond donor) found on the WPF and LPF loops respectively play in maintaining Cpd38 stability. Furthermore, the hydrogen bond acceptor/donator ratio was approximately 4:1 in Cpd38-BRD4 system compared with 2:1 in Cpd38-EP300 system. Taken together, atomistic insights and structural perspectives detailed in this report supplements the experimental report supporting the improved selectivity of Cpd38 for BRD4 ahead of other BCPs while providing leeway for the future design of BET selective agents with better pharmacological profile.
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Affiliation(s)
- Oluwole B Akawa
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Opeyemi S Soremekun
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Fisayo A Olotu
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
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Rohatgi A, Westerterp M, von Eckardstein A, Remaley A, Rye KA. HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research. Circulation 2021; 143:2293-2309. [PMID: 34097448 PMCID: PMC8189312 DOI: 10.1161/circulationaha.120.044221] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.
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Affiliation(s)
- Anand Rohatgi
- Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Marit Westerterp
- Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Arnold von Eckardstein
- Institute of Clinical Chemistry, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland
| | - Alan Remaley
- Section Chief of Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch; National Heart, Lung and Blood Institute, National Institutes of Health; Bethesda, MD
| | - Kerry-Anne Rye
- School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, Australia, 2052
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12
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Dutzmann J, Haertlé M, Daniel JM, Kloss F, Musmann RJ, Kalies K, Knöpp K, Pilowski C, Sirisko M, Sieweke JT, Bauersachs J, Sedding DG, Gegel S. BET bromodomain-containing epigenetic reader proteins regulate vascular smooth muscle cell proliferation and neointima formation. Cardiovasc Res 2021; 117:850-862. [PMID: 32353113 DOI: 10.1093/cvr/cvaa121] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 12/27/2019] [Accepted: 04/23/2020] [Indexed: 12/20/2022] Open
Abstract
AIMS Recent studies revealed that the bromodomain and extra-terminal (BET) epigenetic reader proteins resemble key regulators in the underlying pathophysiology of cancer, diabetes, or cardiovascular disease. However, whether they also regulate vascular remodelling processes by direct effects on vascular cells is unknown. In this study, we investigated the effects of the BET proteins on human smooth muscle cell (SMC) function in vitro and neointima formation in response to vascular injury in vivo. METHODS AND RESULTS Selective inhibition of BETs by the small molecule (+)-JQ1 dose-dependently reduced proliferation and migration of SMCs without apoptotic or toxic effects. Flow cytometric analysis revealed a cell cycle arrest in the G0/G1 phase in the presence of (+)-JQ1. Microarray- and pathway analyses revealed a substantial transcriptional regulation of gene sets controlled by the Forkhead box O (FOXO1)1-transcription factor. Silencing of the most significantly regulated FOXO1-dependent gene, CDKN1A, abolished the antiproliferative effects. Immunohistochemical colocalization, co-immunoprecipitation, and promoter-binding ELISA assay data confirmed that the BET protein BRD4 directly binds to FOXO1 and regulates FOXO1 transactivational capacity. In vivo, local application of (+)-JQ1 significantly attenuated SMC proliferation and neointimal lesion formation following wire-induced injury of the femoral artery in C57BL/6 mice. CONCLUSION Inhibition of the BET-containing protein BRD4 after vascular injury by (+)-JQ1 restores FOXO1 transactivational activity, subsequent CDKN1A expression, cell cycle arrest and thus prevents SMC proliferation in vitro and neointima formation in vivo. Inhibition of BET epigenetic reader proteins might thus represent a promising therapeutic strategy to prevent adverse vascular remodelling.
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MESH Headings
- Animals
- Azepines/pharmacology
- Carotid Artery Injuries/genetics
- Carotid Artery Injuries/metabolism
- Carotid Artery Injuries/pathology
- Cell Cycle Checkpoints
- Cell Cycle Proteins/antagonists & inhibitors
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Proliferation/drug effects
- Cells, Cultured
- Coronary Vessels/drug effects
- Coronary Vessels/metabolism
- Coronary Vessels/pathology
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Disease Models, Animal
- Forkhead Box Protein O1/genetics
- Forkhead Box Protein O1/metabolism
- Heterocyclic Compounds, 4 or More Rings/metabolism
- Humans
- Male
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/injuries
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Neointima
- Nuclear Proteins/antagonists & inhibitors
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Proteins/antagonists & inhibitors
- Proteins/genetics
- Proteins/metabolism
- Signal Transduction
- Transcription Factors/antagonists & inhibitors
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Triazoles/pharmacology
- Vascular System Injuries/genetics
- Vascular System Injuries/metabolism
- Vascular System Injuries/pathology
- Mice
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Affiliation(s)
- Jochen Dutzmann
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Marco Haertlé
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Jan-Marcus Daniel
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Frederik Kloss
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Robert-Jonathan Musmann
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Katrin Kalies
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
| | - Kai Knöpp
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Claudia Pilowski
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
| | - Mirja Sirisko
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Jan-Thorben Sieweke
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Daniel G Sedding
- Mid-Germany Heart Center, Division of Cardiology, Angiology, and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Simona Gegel
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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13
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Brandts J, Ray KK. Apabetalone - BET protein inhibition in cardiovascular disease and Type 2 diabetes. Future Cardiol 2020; 16:385-395. [PMID: 32378426 DOI: 10.2217/fca-2020-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Apabetalone is the first selective BET protein inhibitor in the field of cardiovascular diseases (CVD). BET proteins are epigenetic regulators that link upstream epigenetic modifications to downstream gene expression. Inhibition of BET proteins by apabetalone has been shown to modulate reverse cholesterol transport, coagulation, inflammation and vascular calcification. Furthermore, apabetalone reduces circulating markers of CVD risk and plaque vulnerability. Post-hoc pooled analyses suggest a potential reduction in risk of major adverse cardiac events (MACE) in patients with Type 2 diabetes (T2D) and stable CVD. However, the current cardiovascular outcomes trial BET-on-MACE failed to detect the assumed 30% reduction of MACE by apabetalone in patients with T2D after an acute coronary syndrome.
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Affiliation(s)
- Julia Brandts
- Department of Medicine I, University Hospital RWTH Aachen, Aachen, Germany.,Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, London, UK
| | - Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, London, UK
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14
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Zhang Z, Huang W, Zheng X, Li C, Shen Z. Drug Discovery of Acetophenone Derivatives as BRD4 Inhibitors. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180816666190329223559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
The bromodomain and extra-terminal proteins (BET), in particular BRD4,
has recently emerged as a potential therapeutic target for the treatment of many human disorders
such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more
attention to discover potent BRD4 inhibitors in the past years. In this article, we described the
discovery process of an entirely new chemotype of BRD4 inhibitors.
Methods:
A fragment-based drug discovery strategy was employed in attempting to find a novel
chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with
KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized
based on the interaction revealed by the docking study and the Structure-Activity Relationship
(SAR).
Results:
A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4
with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM, LE > 0.5) based on
virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragmentbased
drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit
nanomolar potency in biochemical assays (IC50 = 0.18 μM).
Conclusion:
The title compounds displayed potent inhibitory activity to BRD4, implying
acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new
chemotype may be promising for developing novel BRD4 inhibitors.
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Affiliation(s)
- Zhimin Zhang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
| | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
| | - Xiaoliang Zheng
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
| | - Chuansheng Li
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
| | - Zhengrong Shen
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China
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15
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Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B. Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors. J Med Chem 2020; 63:3956-3975. [DOI: 10.1021/acs.jmedchem.9b01784] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Zizhou Li
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Senhao Xiao
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China
| | - Yaxi Yang
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Chao Chen
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Tian Lu
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhifeng Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Hualiang Jiang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Shijie Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Cheng Luo
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Bing Zhou
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
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16
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Tonini C, Colardo M, Colella B, Di Bartolomeo S, Berardinelli F, Caretti G, Pallottini V, Segatto M. Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis. Int J Mol Sci 2020; 21:ijms21041297. [PMID: 32075110 PMCID: PMC7072965 DOI: 10.3390/ijms21041297] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/08/2020] [Accepted: 02/13/2020] [Indexed: 12/19/2022] Open
Abstract
The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis.
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Affiliation(s)
- Claudia Tonini
- Department of Science, University of Rome “Roma Tre”, Viale Marconi 446, 00146 Rome, Italy; (C.T.); (F.B.); (V.P.)
| | - Mayra Colardo
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (Is), Italy; (M.C.); (B.C.); (S.D.B.)
| | - Barbara Colella
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (Is), Italy; (M.C.); (B.C.); (S.D.B.)
| | - Sabrina Di Bartolomeo
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (Is), Italy; (M.C.); (B.C.); (S.D.B.)
| | - Francesco Berardinelli
- Department of Science, University of Rome “Roma Tre”, Viale Marconi 446, 00146 Rome, Italy; (C.T.); (F.B.); (V.P.)
| | - Giuseppina Caretti
- Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy;
| | - Valentina Pallottini
- Department of Science, University of Rome “Roma Tre”, Viale Marconi 446, 00146 Rome, Italy; (C.T.); (F.B.); (V.P.)
| | - Marco Segatto
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (Is), Italy; (M.C.); (B.C.); (S.D.B.)
- Correspondence:
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17
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Li X, Liao J, Jiang Z, Liu X, Chen S, He X, Zhu L, Duan X, Xu Z, Qi B, Guo X, Tong R, Shi J. A concise review of recent advances in anti-heart failure targets and its small molecules inhibitors in recent years. Eur J Med Chem 2020; 186:111852. [PMID: 31759729 DOI: 10.1016/j.ejmech.2019.111852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 11/30/2022]
Abstract
Heart failure is a disease with high mortality and the risk of heart failure increases in magnitude with age. The patients of heart failure is increasing year by year. Hence, Pharmaceutical researchers have to develop new drugs with better pharmacological effects to coping with this phenomenon. In this article, we reviewed the small molecule compounds for heart failure that have been marketed in recent years or are promising to enter clinical research. We also reviewed the SAR (structure activity relationship) of these molecules, such as renin inhibitors, ROMK inhibitors, a kind of new diuretics, and some dual-targets inhibitors. These small molecules proven to be beneficial effect on heart failure patients. Which may provide ideas for the design of novel anti-heart failure therapeutic drugs.
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Affiliation(s)
- Xingxing Li
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China
| | - Jing Liao
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China; Pediatric Department Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, People's Republic of China, Chengdu, 610072, China
| | - Zhongliang Jiang
- Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Xinyu Liu
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China
| | - Shan Chen
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China
| | - Xia He
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China; Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Individual Key Laboratory, Chengdu, People's Republic of China, Chengdu, 610072, China
| | - Ling Zhu
- Eastern Hospital, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Xingmei Duan
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China; Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Individual Key Laboratory, Chengdu, People's Republic of China, Chengdu, 610072, China
| | - Zhuyu Xu
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China
| | - Baowen Qi
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Xiaoqiang Guo
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Rongsheng Tong
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China; Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Individual Key Laboratory, Chengdu, People's Republic of China, Chengdu, 610072, China.
| | - Jianyou Shi
- School of Medicine, University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, 610054, China; Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Individual Key Laboratory, Chengdu, People's Republic of China, Chengdu, 610072, China.
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18
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Hilton-Proctor J, Ilyichova O, Zheng Z, Jennings I, Johnstone R, Shortt J, Mountford S, Scanlon M, Thompson P. Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition. Bioorg Med Chem 2019; 27:115157. [DOI: 10.1016/j.bmc.2019.115157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 01/24/2023]
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19
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Kosmas CE, Sourlas A, Silverio D, Montan PD, Guzman E. Novel lipid-modifying therapies addressing unmet needs in cardiovascular disease. World J Cardiol 2019; 11:256-265. [PMID: 31798792 PMCID: PMC6885448 DOI: 10.4330/wjc.v11.i11.256] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 08/22/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) remains a major cause of morbidity and mortality worldwide. Currently, it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD. Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality. In addition, recent advances in lipid-modifying therapies, such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors, have further improved cardiovascular outcomes in patients with hypercholesterolemia. However, despite significant progress in the treatment of dyslipidemia, there is still considerable residual risk of recurring cardiovascular events. Furthermore, in some cases, an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date. Thus, a number of novel pharmacological interventions are under early human trials, targeting different molecular pathways of lipid formation, regulation and metabolism. This editorial aims to discuss the current clinical and scientific data on new promising lipid-modifying therapies addressing unmet needs in CVD, which may prove beneficial in the near future.
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Affiliation(s)
- Constantine E Kosmas
- Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY 10467, United States
| | - Andreas Sourlas
- School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Delia Silverio
- Cardiology Clinic, Cardiology Unlimited, PC, New York, NY 10033, United States
| | - Peter D Montan
- Cardiology Clinic, Cardiology Unlimited, PC, New York, NY 10033, United States
| | - Eliscer Guzman
- Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY 10467, United States
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20
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Ray KK, Nicholls SJ, Ginsberg HD, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Toth PP, Wong N, Cummings JL, Sweeney M, Schwartz GG. Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial. Am Heart J 2019; 217:72-83. [PMID: 31520897 DOI: 10.1016/j.ahj.2019.08.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 08/01/2019] [Indexed: 12/26/2022]
Abstract
After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN: Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY: BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.
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21
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Fontecha-Barriuso M, Martin-Sanchez D, Ruiz-Andres O, Poveda J, Sanchez-Niño MD, Valiño-Rivas L, Ruiz-Ortega M, Ortiz A, Sanz AB. Targeting epigenetic DNA and histone modifications to treat kidney disease. Nephrol Dial Transplant 2019. [PMID: 29534238 DOI: 10.1093/ndt/gfy009] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease. A beneficial in vivo effect over preclinical kidney injury has been reported for drugs that decrease DNA methylation by either inhibiting DNA methylation (e.g. 5-azacytidine and decitabine) or activating DNA demethylation (e.g. hydralazine), decrease histone methylation by inhibiting histone methyltransferases, increase histone acetylation by inhibiting histone deacetylases (HDACs, e.g. valproic acid, vorinostat, entinostat), increase histone crotonylation (crotonate) or interfere with histone modification readers [e.g. inhibits of bromodomain and extra-terminal proteins (BET)]. Most preclinical studies addressed CKD or the AKI-to-CKD transition. Crotonate administration protected from nephrotoxic AKI, but evidence is conflicting on DNA methylation inhibitors for preclinical AKI. Several drugs targeting epigenetic regulators are in clinical development or use, most of them for malignancy. The BET inhibitor apabetalone is in Phase 3 trials for atherosclerosis, kidney function being a secondary endpoint, but nephrotoxicity was reported for DNA and HDAC inhibitors. While research into epigenetic modulators may provide novel therapies for kidney disease, caution should be exercised based on the clinical nephrotoxicity of some drugs.
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Affiliation(s)
- Miguel Fontecha-Barriuso
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Diego Martin-Sanchez
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Olga Ruiz-Andres
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Jonay Poveda
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Lara Valiño-Rivas
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Marta Ruiz-Ortega
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Alberto Ortiz
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Ana Belén Sanz
- Research Institute IIS-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,IRSIN, Madrid, Spain.,REDINREN, Madrid, Spain
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22
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Abstract
Less than a decade ago, it was shown that bromodomains, acetyl lysine 'reader' modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein-protein or protein-peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.
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23
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Abstract
Bromodomain and extra-terminal (BET) inhibitors, acting via epigenetic mechanisms, have been developed recently as potential new treatments for cancer, including prostate cancer, and inflammatory conditions. Some BET inhibitors, such as RVX-208, also raise high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 levels. A recent meta-analysis of three small trials (n = 798) found that RVX-208 protected against major adverse cardiovascular events (MACE), raising the question as to whether this protective effect was an artefact, a chance finding, or mediated by HDL-C, anti-inflammatory pathways, or other factors. Notably, the effect of RVX-208 on MACE was largely driven by revascularizations, but fewer interventions in the treatment arm could have arisen accidently from favorable effects of RVX-208 on HDL-C and C-reactive protein influencing decisions about patient care. A larger (n = 2400) trial of RVX-208, BETonMACE (NCT02586155), with a more restricted definition of MACE, excluding hospitalizations, will shortly provide clarity. A successful BETonMACE trial would raise the question as to whether RVX-208 operates via lipids, inflammation, or other means, because several previous HDL-C modulators and anti-inflammatories have not provided effective means of treating cardiovascular disease and reducing overall mortality. Re-conceptualizing cardiovascular disease within the well-established evolutionary biology theory that growth and specifically reproduction trade-off against longevity might provide a more comprehensive explanation. Drivers of the gonadotropic axis, particularly androgens, suppress both HDL-C and the immune system while promoting ischemic heart disease and stroke. As such, any effects of RVX-208 on cardiovascular disease might be the result of reducing androgens, of which higher HDL-C and reduced inflammation are biomarkers. Notably, several other effective treatments for cardiovascular disease, such as statins and spironolactone, are known anti-androgens. Results of the BETonMACE trial, and corresponding insight about the mechanism of BET inhibitors in cardiovascular disease, are eagerly awaited.
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24
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Agrawal P, Heimbruch KE, Rao S. Genome-Wide Maps of Transcription Regulatory Elements and Transcription Enhancers in Development and Disease. Compr Physiol 2018; 9:439-455. [PMID: 30549021 DOI: 10.1002/cphy.c180028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gene expression is regulated by numerous elements including enhancers, insulators, transcription factors, and architectural proteins. Regions of DNA distal to the transcriptional start site, called enhancers, play a central role in the temporal and tissue-specific regulation of gene expression through RNA polymerase II. The identification of enhancers and other cis regulatory elements has largely been possible due to advances in next generation sequencing technologies. Enhancers regulate gene expression through chromatin loops mediated by architectural proteins such as YY1, CTCF, the cohesin complex, and LDB1. Additionally, enhancers can be transcribed to produce noncoding RNAs termed enhancer RNAs that likely participate in transcriptional regulation. The central role of enhancers in regulating gene expression implicates them in both normal physiology but also many disease states. The importance of enhancers is evident by the suggested role of SNPs, duplications, and other alterations of enhancer function in many diseases, ranging from cancer to atherosclerosis to chronic kidney disease. Although much progress has been made in recent years, the field of enhancer biology and our knowledge of the cis regulome remains a work in progress. This review will highlight recent seminal studies which demonstrate the role of enhancers in normal physiology and disease pathogenesis. © 2019 American Physiological Society. Compr Physiol 9:439-455, 2019.
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Affiliation(s)
- Puja Agrawal
- Blood Research Institute, BloodCenter of Wisconsin, a part of Versiti, Milwaukee, Wisconsin, USA.,Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Katelyn E Heimbruch
- Blood Research Institute, BloodCenter of Wisconsin, a part of Versiti, Milwaukee, Wisconsin, USA.,Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Sridhar Rao
- Blood Research Institute, BloodCenter of Wisconsin, a part of Versiti, Milwaukee, Wisconsin, USA.,Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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25
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Zhao Y, Zhou B, Bai L, Liu L, Yang CY, Meagher JL, Stuckey JA, McEachern D, Przybranowski S, Wang M, Ran X, Aguilar A, Hu Y, Kampf JW, Li X, Zhao T, Li S, Wen B, Sun D, Wang S. Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor. J Med Chem 2018; 61:6110-6120. [PMID: 30015487 DOI: 10.1021/acs.jmedchem.8b00483] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.
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26
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Ghosh GC, Bhadra R, Ghosh RK, Banerjee K, Gupta A. RVX 208: A novel BET protein inhibitor, role as an inducer of apo A-I/HDL and beyond. Cardiovasc Ther 2018; 35. [PMID: 28423226 DOI: 10.1111/1755-5922.12265] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 12/17/2016] [Accepted: 04/13/2017] [Indexed: 12/28/2022] Open
Abstract
Low-density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high-density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of proinflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis. RVX 208 is a novel, orally active, BET protein inhibitor and the only BET inhibitor currently available in the field of atherosclerosis. RVX 208 acts primarily by increasing apo A-I (apolipoprotein A-I) and HDL levels. RVX 208 has a novel action of increasing larger, more cardio-protective HDL particles. Post hoc analysis of Phase II trials also showed that RVX 208 reduced major adverse cardiovascular events (MACE) in treated patients, over and above that of apo A-I/HDL increasing action. This MACE reducing actions of RVX 208 were largely due to its novel anti-inflammatory actions. Currently, a phase III trial, BETonMACE, is recruiting patients to look for the effects of RVX 208 in patients with increased risk of atherosclerotic cardiovascular disease. So BET inhibitors act in multiple ways to inhibit and modulate atherosclerosis and would be an emerging and potential option in the management of multifactorial disease like coronary artery disease by inhibiting a single substrate. But we need long-term phase III trial data's to look for effects on real-world patients.
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Affiliation(s)
- Gopal C Ghosh
- Department of Cardiology, Christian Medical College, Vellore, India
| | - Rajarshi Bhadra
- Department of Medicine, St. Vincent Charity Medical Center, A Teaching Hospital of Case Western Reserve University, Cleveland, OH, USA
| | - Raktim K Ghosh
- Department of Cardiovascular Medicine, St. Vincent Charity Medical Center, A Teaching Hospital of Case Western Reserve University, Cleveland, OH, USA
| | | | - Anjan Gupta
- Department of Cardiovascular Medicine, St. Vincent Charity Medical Center, A Teaching Hospital of Case Western Reserve University, Cleveland, OH, USA
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27
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Tsimihodimos V, Elisaf M. Effects of evolving lipid-lowering drugs on carbohydrate metabolism. Diabetes Res Clin Pract 2018; 137:1-9. [PMID: 29278710 DOI: 10.1016/j.diabres.2017.12.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/05/2017] [Accepted: 12/18/2017] [Indexed: 01/05/2023]
Abstract
The understanding that statins reduce but not eliminate the cardiovascular risk associated with disturbed lipid metabolism and the existence of forms of dyslipidemia that are unresponsive or only partially responsive to statins have led to the development of many novel lipid-lowering drugs. Accumulating evidence suggests that the interplay between carbohydrate and lipid metabolism is bidirectional. Thus, any intervention that affects lipid metabolism has the potential to influence the homeostasis of glucose. In this review we summarize the available data on the effects of the evolving lipid-lowering drugs on carbohydrate metabolism.
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Affiliation(s)
- V Tsimihodimos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
| | - M Elisaf
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
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28
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Haas MJ, Plazarte M, Chamseddin A, Onstead-Haas L, Wong NCW, Plazarte G, Mooradian AD. Inhibition of hepatic apolipoprotein A-I gene expression by histamine. Eur J Pharmacol 2018; 823:49-57. [PMID: 29378195 DOI: 10.1016/j.ejphar.2018.01.035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 01/17/2018] [Accepted: 01/23/2018] [Indexed: 01/12/2023]
Abstract
In a recent high throughput analysis to identify drugs that alter hepatic apolipoprotein A-I (apo A-I) expression, histamine receptor one (H1) antagonists emerged as potential apo A-1 inducing drugs. Thus the present study was undertaken to identify some of the underlying molecular mechanisms of the effect of antihistaminic drugs on apo AI production. Apo A-I levels were measured by enzyme immunoassay and Western blots. Apo A-I mRNA levels were measured by reverse transcription real-time PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as the internal control. The effects of histamine and antihistamines on apo A-I gene were determined by transient transfection of plasmids containing the apo A-I gene promoter. Histamine repressed while (H1) receptor antagonist azelastine increased apo A-I protein and mRNA levels within 48 h in a dose-dependent manner. Azelastine and histamine increased and suppressed, respectively, apo A-I gene promoter activity through a peroxisome proliferator activated receptor α response element. Treatment of HepG2 cells with other H1 receptor antagonists including fexofenadine, cetirizine, and diphenhydramine increased apo A-I levels in a dose-dependent manner while treatment with H2 receptor antagonists including cimetidine, famotidine, and ranitidine had no effect. We conclude that H1 receptor signaling is a novel pathway of apo A1 gene expression and therefore could be an important therapeutic target for enhancing de-novo apo A-1 synthesis.
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Affiliation(s)
- Michael J Haas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States.
| | - Monica Plazarte
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States
| | - Ayham Chamseddin
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States
| | - Luisa Onstead-Haas
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States
| | - Norman C W Wong
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Gabriela Plazarte
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States
| | - Arshag D Mooradian
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, 653-1 West 8th Street L14, Jacksonville, FL 32209, United States
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29
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Baye E, Ukropec J, de Courten MP, Vallova S, Krumpolec P, Kurdiova T, Aldini G, Ukropcova B, de Courten B. Effect of carnosine supplementation on the plasma lipidome in overweight and obese adults: a pilot randomised controlled trial. Sci Rep 2017; 7:17458. [PMID: 29234057 PMCID: PMC5727174 DOI: 10.1038/s41598-017-17577-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 11/22/2017] [Indexed: 12/20/2022] Open
Abstract
Carnosine has been shown to reduce oxidation and glycation of low density lipoprotein hence improving dyslipidaemia in rodents. The effect of carnosine on human plasma lipidome has thus far not been investigated. We aimed to determine whether carnosine supplementation improves the plasma lipidome in overweight and obese individuals. Lipid analysis was performed by liquid chromatography mass spectrometry in 24 overweight and obese adults: 13 were randomly assigned to 2 g carnosine daily and 11 to placebo, and treated for 12 weeks. Carnosine supplementation maintained trihexosylceramide (0.01 ± 0.19 vs -0.28 ± 0.34 nmol/ml, p = 0.04), phosphatidylcholine (77 ± 167 vs -81 ± 196 nmol/ml, p = 0.01) and free cholesterol (20 ± 80 vs -69 ± 80 nmol/ml, p = 0.006) levels compared to placebo. Trihexosylceramide was inversely related with fasting insulin (r = -0.6, p = 0.002), insulin resistance (r = -0.6, p = 0.003), insulin secretion (r = -0.4, p = 0.05) and serum carnosinase 1 activity (r = -0.3, p = 0.05). Both phosphatidylcholine and free cholesterol did not correlate with any cardiometabolic parameters. Our data suggest that carnosine may have beneficial effects on the plasma lipidome. Future larger clinical trials are needed to confirm this.
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Affiliation(s)
- Estifanos Baye
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maximilian Pj de Courten
- Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia
| | - Silvia Vallova
- Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Patrik Krumpolec
- Institute of Experimental Endocrinology, Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Timea Kurdiova
- Institute of Experimental Endocrinology, Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Barbara Ukropcova
- Institute of Experimental Endocrinology, Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia.,Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
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30
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Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease. Mol Cell Biochem 2017; 440:167-187. [PMID: 28828539 DOI: 10.1007/s11010-017-3165-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 08/16/2017] [Indexed: 12/17/2022]
Abstract
Coronary artery disease, the leading cause of death in the developed and developing countries, is prevalent in diabetes mellitus with 68% cardiovascular disease (CVD)-related mortality. Epidemiological studies suggested inverse correlation between HDL and CVD occurrence. Therefore, low HDL concentration observed in diabetic patients compared to non-diabetic individuals was thought to be one of the primary causes of increased risks of CVD. Efforts to raise HDL level via CETP inhibitors, Torcetrapib and Dalcetrapib, turned out to be disappointing in outcome studies despite substantial increases in HDL-C, suggesting that factors beyond HDL concentration may be responsible for the increased risks of CVD. Therefore, recent studies have focused more on HDL function than on HDL levels. The metabolic environment in diabetes mellitus condition such as hyperglycemia-induced advanced glycation end products, oxidative stress, and inflammation promote HDL dysfunction leading to greater risks of CVD. This review discusses dysfunctional HDL as one of the mechanisms of increased CVD risks in diabetes mellitus through adversely affecting components that support HDL function in cholesterol efflux and LDL oxidation. The dampening of reverse cholesterol transport, a key process that removes cholesterol from lipid-laden macrophages in the arterial wall, leads to increased risks of CVD in diabetic patients. Therapeutic approaches to keep diabetes under control may benefit patients from developing CVD.
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31
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Smolders L, Plat J, Mensink RP. Dietary Strategies and Novel Pharmaceutical Approaches Targeting Serum ApoA-I Metabolism: A Systematic Overview. J Nutr Metab 2017; 2017:5415921. [PMID: 28695008 PMCID: PMC5485365 DOI: 10.1155/2017/5415921] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/16/2017] [Indexed: 12/19/2022] Open
Abstract
The incidence of CHD is still increasing, which underscores the need for new preventive and therapeutic approaches to decrease CHD risk. In this respect, increasing apoA-I concentrations may be a promising approach, especially through increasing apoA-I synthesis. This review first provides insight into current knowledge on apoA-I production, clearance, and degradation, followed by a systematic review of dietary and novel pharmacological approaches to target apoA-I metabolism. For this, a systematic search was performed to identify randomized controlled intervention studies that examined effects of whole foods and (non)nutrients on apoA-I metabolism. In addition, novel pharmacological approaches were searched for, which were specifically developed to target apoA-I metabolism. We conclude that both dietary components and pharmacological approaches can be used to increase apoA-I concentrations or functionality. For the dietary components in particular, more knowledge about the underlying mechanisms is necessary, as increasing apoA-I per se does not necessarily translate into a reduced CHD risk.
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Affiliation(s)
- Lotte Smolders
- Department of Human Biology and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, Netherlands
| | - Jogchum Plat
- Department of Human Biology and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, Netherlands
| | - Ronald P. Mensink
- Department of Human Biology and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, Netherlands
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32
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Gul S. Epigenetic assays for chemical biology and drug discovery. Clin Epigenetics 2017; 9:41. [PMID: 28439316 PMCID: PMC5399855 DOI: 10.1186/s13148-017-0342-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 04/12/2017] [Indexed: 12/27/2022] Open
Abstract
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects. The current clinical trials involving the next generation of epigenetic drugs may address the disadvantages of the currently approved epigenetic drugs. The identification of chemical starting points of many drugs often makes use of screening in vitro assays against libraries of synthetic or natural products. These assays can be biochemical (using purified protein) or cell-based (using for example, genetically modified, cancer cell lines or primary cells) and performed in microtiter plates, thus enabling a large number of samples to be tested. A considerable number of such assays are available to monitor epigenetic target activity, and this review provides an overview of drug discovery and chemical biology and describes assays that monitor activities of histone deacetylase, lysine-specific demethylase, histone methyltransferase, histone acetyltransferase and bromodomain. It is of critical importance that an appropriate assay is developed and comprehensively validated for a given drug target prior to screening in order to improve the probability of the compound progressing in the drug discovery value chain.
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Affiliation(s)
- Sheraz Gul
- Fraunhofer Institute for Molecular Biology and Applied Ecology - ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany
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33
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Abstract
INTRODUCTION Cardiovascular morbidity and mortality are of increasing concern, not only to patients but also to the health care profession and service providers. The preventative benefit of treatment of dyslipidaemia is unquestioned but there is a large, so far unmet need to improve clinical outcome. There are exciting new discoveries of targets that may translate into improved clinical outcome. Areas covered: This review highlights some new pathways in cholesterol and triglyceride metabolism and examines new targets, new drugs and new molecules. The review includes the results of recent trials of relatively new drugs that have shown benefit in cardiovascular endpoint outcomes, drugs that have been licenced without endpoint trials yet available and new drugs that have not yet been licenced but have produced exciting results in animal studies and some in early phase 2 human studies. Expert opinion: The new areas that have been discovered as the cause of dyslipidaemia have opened up a host of new targets for new drugs including antisense RNA's, microRNA's and human monoclonal antibodies. The plethora of new targets and new drugs has made it an extraordinarily exciting time in the development of therapeutics to combat atherosclerosis.
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Affiliation(s)
- Gerald H Tomkin
- a Diabetes Institute of Ireland , Beacon Clinic and Trinity College , Dublin 2 , Ireland
| | - Daphne Owens
- a Diabetes Institute of Ireland , Beacon Clinic and Trinity College , Dublin 2 , Ireland
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34
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Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration. J Neuroinflammation 2017; 14:14. [PMID: 28103888 PMCID: PMC5248448 DOI: 10.1186/s12974-016-0775-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Accepted: 12/07/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) "read" (bind) histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation. These epigenetic "readers" play crucial roles in pathogenic processes such as inflammation. The role of BETs in influencing the degenerative process in the retina is however unknown. METHODS We employed the rd10 mouse model (Pde6b rd10 mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration. RESULTS Inhibition of BET activity by intravitreal delivery of JQ1, a BET-specific inhibitor binding both Brom1 and Brom2, ameliorated photoreceptor degeneration and improved electroretinographic function. Rescue effects of JQ1 were related to the suppression of retinal microglial activation in vivo, as determined by decreased immunostaining of activation markers (IBA1, CD68, TSPO) and messenger RNA (mRNA) levels of inflammatory cytokines in microglia purified from rd10 retinas. JQ1 pre-treatment also suppressed microglial activation in vitro, decreasing microglial proliferation, migration, and mRNA expression of inflammatory cytokines (TNFα, MCP-1, IL-1β, IL-6, and RANTES). Expression of BET2, but not BET3 and BET4, was significantly elevated during photoreceptor degeneration at postnatal day (PN)24 in retinas of rd10 mice relative to age-matched wild-type controls. siRNA knockdown of BET2 but not BET4, and the inhibitor of Brom2 (RVX208) but not of Brom1 (Olinone), decreased microglial activation. CONCLUSIONS These findings indicate that BET inhibition rescues photoreceptor degeneration likely via the suppression of microglial activation and implicates BET interference as a potential therapeutic strategy for the treatment of degenerative retinal diseases.
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35
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Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development. Microbiol Mol Biol Rev 2017; 81:81/1/e00047-16. [PMID: 28077462 DOI: 10.1128/mmbr.00047-16] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.
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Abstract
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.
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Affiliation(s)
- Montserrat Pérez-Salvia
- a Cancer Epigenetics and Biology Program (PEBC) , Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Catalonia , Spain
| | - Manel Esteller
- a Cancer Epigenetics and Biology Program (PEBC) , Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Catalonia , Spain.,b Department of Physiological Sciences II, School of Medicine , University of Barcelona , Barcelona , Catalonia , Spain.,c Institució Catalana de Recerca i Estudis Avançats (ICREA) , Barcelona , Catalonia , Spain
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