Aberrant activation of the stimulator of interferon genes (STING) pathway is associated with the development of various inflammatory and autoimmune diseases. Targeting STING for degradation represents a novel strategy for the treatment of these diseases. In this study, we designed and synthesized a series of STING-PROTACs based on a nitro-free covalent warhead and different E3 ligase binders. The representative compound 2h specifically degraded STING protein through the proteasome pathway with a DC50 value of 3.23 μM and exhibited sustained degradation activity over 72 h. Further biological studies demonstrated that compound 2h inhibited STING signaling and effectively suppressed immune-inflammatory cytokines both in vitro and in vivo. Moreover, compound 2h offered better safety compared to its warhead molecule and SP23. Collectively, compound 2h is a potent nitro-free covalent STING degrader and warrants further investigation.

Thalidomide has been used as a repurposed drug for treating multiple myeloma since 1997. Several novel anticancer drugs containing thalidomide active moiety has been discovered since then. Many thalidomide drug candidates with tuned linker size have been instrumental in inhibiting histone deacetylase, kinase, transcription factors etc. and facilitate selective degradation of E3 ligase and other enzymes. Here we are focused on small molecule degraders that are being tailored with tweaking synthetic architectures around thalidomide chemical motif towards the development of promising drug candidates. Interesting biomedical applications of thalidomide-based degraders with recent developments including pharmacokinetic profiles, protein stability, activity studies, degradation assays, and antitumor response are elucidated.

Constant activation of stimulator of interferon genes (STING), resulting from aberrant metabolism or mutations in STING1, can initiate inflammatory damage or autoimmune disease. STING antagonists have the potential to be used as therapeutics for inflammatory and autoimmune diseases. Based on the structures of the covalent STING inhibitor H151 and C178, we designed, synthesized, and evaluated a novel series of indole derivatives for STING inhibition. Several compounds exhibited efficacious STING inhibitory activity. One of these novel chemical entities, 4dc, was more potent than H151, with IC50 values of 0.14 μM in RAW-LuciaTM ISG cells and 0.39 μM in THP1-Dual™ cells. The compound effectively relieved the symptoms of renal injury in a cisplatin-induced acute kidney injury mouse model. Compound 4dc represents a new chemotype of STING inhibitor that deserves further investigation as anti-inflammatory agent.

The regulation of the STING (stimulator of interferon genes) pathway represents a promising target for a range of inflammatory diseases. This review provides an overview of the structure of STING and discusses the mechanisms by which the cyclic GMP-AMP synthase (cGAS)-STING pathway is associated with various autoinflammatory and autoimmune diseases. We explore how targeting STING inhibition or degradation can alleviate excessive inflammatory signaling and improve efficacy. Emerging strategies include inhibiting STING expression by covalently binding compounds or using ligands that target the binding pocket. In addition, selective degradation of STING via the ubiquitin-proteasome system or the lysosomal pathway shows promise. In addition, we explore the implications of modulating the cGAS-STING pathway in the context of various inflammatory diseases. Finally, we summarize the chemical properties of recently developed STING compounds and their potential clinical applications. By comprehensively reviewing the current understanding of the role of STING in inflammation and the therapeutic potential of targeting STING, we aim to identify new avenues of intervention that could improve outcomes for patients with inflammatory diseases. This review highlights the important role of STING in the regulation of inflammation and its potential as a target for innovative therapeutic strategies.

Acute kidney injury (AKI) is a critical condition resulting from intrinsic immune overactivation for which no ideal therapeutic agent is available. The development of therapeutic drugs with new targets and mechanism has become one of the important challenges in the pharmaceutical field. The interferon gene stimulating protein (STING) directly regulates the intrinsic immune processes and is a potential target for AKI therapy. Herein, we designed synthesized and evaluated a series of novel STING-PROTAC degraders via a rigid strategy. Among them, compound ST9 performed the highest degradation capacity with a DC50 of 0.62 μM in THP-1 cells. In a cisplatin-induced HK-2 cell model, ST9 could down-regulate the STING/NF-κB signaling axis and thus inhibit the expression of inflammatory factors. Additionally, ST9 showed a significantly improved metabolic stability profile. Furthermore, ST9 displayed favorable in vivo anti-AKI efficacy and has no toxic side effects on other organs. These results suggest that the novel rigid STING-PROTAC ST9 has clinical potential as a renoprotective agent for the treatment/prevention of acute kidney injury.

Stimulating the STING signaling pathway for immune system activation is considered a promising strategy for cancer treatment. However, activating the STING pathway can lead to adverse effects, as aberrant activation or specific mutations in STING may result in autoimmune and inflammatory diseases. Therefore, the development of STING inhibitors is equally important. In this study, we first introduced hydroxyl groups into the STING inhibitors C170 and H151, creating functional sites for further modification. Then the introduction of various substituents resulted in the identification of more potent inhibitors, Y2 and HY2, which effectively suppressed the activation of the STING pathway in THP1 and RAW264.7 cells. Compounds Y2 and HY2 demonstrated potent anti-inflammatory effects in mice cisplatin-induced acute kidney injury models by inhibiting the STING pathway. Collectively, Y2 and HY2 warrant further investigation as novel anti-inflammatory agents.

Proteolysis-targeting chimera (PROTAC) technology was employed to achieve the degradation of PI3Kδ in this study, and a series of PROTAC-based PI3Kδ degraders were first developed. Lysine-targeted covalent strategy led to the discovery of novel potent PROTAC-based PI3Kδ degraders. After screening and structure-activity relationship study, B14 was optimal and exhibited strong antiproliferation and selective PI3Kδ inhibition, with a high degradation value (DC50 = 3.98 nM). B14 induced cell cycle arrest in the premitotic phase and prompted cell apoptosis. B14 displayed effective suppression of the tumor growth in the xenograft model and significantly promoted the PI3Kδ degradation in vivo. Most importantly, B14 bound to the Lys779 of PI3Kδ to selectively degrade PI3Kδ by covalent-bonding. Mechanistic studies indicated that the ubiquitin-proteasome pathway was involved in the degradation process. This study provided an effective approach for developing PROTAC-based PI3Kδ degraders, and the lysine-targeted covalent strategy laid the foundation for the further design of potent PI3Kδ-targeting PROTACs.

Nisin, derived from Streptococcus lactis, is the only approved bacteriocin for food preservation. With wide application in multitudinous food, progressively increasing studies have focused on its anti-inflammatory activity, while its structure-effect relationship and molecular mechanism remain unclear. In this study, the anti-inflammatory efficiency and structural differences of two typical types of nisin, A and Z, were first compared based on a mouse model. The self-assembly behavior of nisin was uncovered, and the characteristics of the self-assembled nanoscale nisin were explored. Based on the transcriptomic analysis, the anti-inflammatory mechanisms of the ribosomal pathway activation of both nisin A and nisin Z were further analyzed, and the upregulation of atp7b and entpd4 triggered by A and Z, respectively, and the consequent adenosine production levels elucidated the therapeutic differences. This study deepens the understanding of the structural and molecular mechanisms underlying the anti-inflammatory activity of nisin and provides an innovative horizon for the future application of nisin.

Given the critical role of STING in autoimmune and inflammatory disorders, the development of targeted small-molecule inhibitors has been a promising strategy for the treatment of these diseases. Nevertheless, the currently reported STING inhibitors suffer from limited structural diversity, species sensitivity, and poor activity; therefore, none are suitable for clinical investigation. Herein, we performed a structural modification campaign on the tool compound 6 (H-151) based on its potential metabolic hotspots. Compound 66, bearing a difluorobenzodioxol moiety, was identified as one of the most potent STING inhibitors with IC50 values of 116 and 96.3 nM for h- and m-STING, respectively. This compound exhibited a notable enhancement in metabolic properties, especially in terms of metabolic stability. A mechanism study verified that 66 engaged with STING in a covalent manner akin to that of 6. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, 66 significantly alleviated tissue injury and inflammation.

Inflammations are innate and adaptive immune responses that get instigated in reciprocation to infection. However, if left unchecked, they pose a formidable challenge in clinical settings. In search of user-friendly solutions, our work delineated a rational combinatorial strategy, harnessing chiral orchestration in a triphenylalanine fragment and appending it to δ-amino valeric acid at the N-terminus (hydrogelators I-VIII) such that a potential matrix metalloproteinase-2 (MMP2) inhibitor could be fished out from the design. Our rigorous investigations revealed that from a pool of eight constructs, hydrogelator VIII, with a DLL configuration at the triphenylalanines, displayed excellent MMP2 inhibitory activities in vitro, which was further supported by molecular modelling studies. Besides, the β-sheet structured scaffold not only showed substantial antibacterial efficacy against the Gram-positive pathogens S. aureus, S. mutans, B. subtilis and E. fecalis but also exhibited proteolytic stability and biocompatibility towards mammalian cells. Furthermore, the scaffold possessed high mechanical strength at physiological pH and mechanical stress-triggered gel-sol-gel transition properties. Finally, the in vivo efficacy was evaluated using an air pouch model of acute inflammation in albino mice that certified hydrogelator VIII as a promising anti-inflammatory therapeutic to pave the path for future healthcare management.

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates in AD-related neuroinflammation and neurodegeneration. A substantial body of evidence indicates that mitochondria are involved in the critical pathogenic mechanisms of AD, whose damage leads to the release of mitochondrial DNA (mtDNA) into the extramitochondrial space. This leaked mtDNA serves as a DAMP, activating various pattern recognition receptors and immune defense networks in the brain, including the cGAS-STING pathway, ultimately leading to an imbalance in immune homeostasis. Therefore, modulation of the mtDNA-cGAS-STING pathway to restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In this review, we focus on the mechanisms of mtDNA release during stress and the activation of the cGAS-STING pathway. Additionally, we delve into the research progress on this pathway in AD, and further discuss the primary directions and potential hurdles in developing targeted therapeutic drugs, to gain a deeper understanding of the pathogenesis of AD and provide new approaches for its therapy.

Cancer immunoediting is a dynamic process of tumor-immune system interaction that plays a critical role in cancer development and progression. Recent studies have highlighted the importance of innate signaling pathways possessed by both cancer cells and immune cells in this process. The STING molecule, a pivotal innate immune signaling molecule, mediates DNA-triggered immune responses in both cancer cells and immune cells, modulating the anti-tumor immune response and shaping the efficacy of immunotherapy. Emerging evidence has shown that the activation of STING signaling has dual opposing effects in cancer progression, simultaneously provoking and restricting anti-tumor immunity, and participating in every phase of cancer immunoediting, including immune elimination, equilibrium, and escape. In this review, we elucidate the roles of STING in the process of cancer immunoediting and discuss the dichotomous effects of STING agonists in the cancer immunotherapy response or resistance. A profound understanding of the sophisticated roles of STING signaling pathway in cancer immunoediting would potentially inspire the development of novel cancer therapeutic approaches and overcome the undesirable protumor effects of STING activation.

The cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway plays a key role in triggering interferon and inflammatory responses against microbial invasion or tumor. However, aberrant activation of the cGAS-STING pathway is associated with a variety of inflammatory and autoimmune diseases, and thus inhibition of STING is regarded as a potential new approach to treating these diseases. Herein, we report a series of novel indolyl-urea derivatives as STING inhibitors. The representative compound 42 exhibited potent STING inhibitory activity, acceptable pharmacokinetic properties, and good in vivo safety profiles. Mechanistically, 42 could block the palmitoylation of the STING protein and STING downstream signaling. Importantly, oral administration of 42 could effectively suppress STING-mediated inflammation in 10-carboxymethyl-9-acridanone (CMA)-treated mouse and Trex1-/- mouse. Together, compound 42 represents a promising STING inhibitor for treating STING-associated inflammatory and autoimmune diseases.

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering a method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" proteins. This concept, pioneered by Crews and his team, introduced the use of small molecules to link a target protein to an E3 ubiquitin ligase, inducing ubiquitination and subsequent degradation of the target protein. By promoting protein degradation rather than merely inhibiting function, PROTACs present a novel therapeutic strategy with enhanced specificity and effectiveness, especially in areas such as cancer and neurodegenerative diseases. Since their initial discovery, the field of PROTAC research has rapidly expanded with numerous PROTACs now designed to target a wide range of disease-relevant proteins. The substantial research, investment, and collaboration across academia and the pharmaceutical industry reflect the growing interest in PROTACs. This Review discusses the journey of PROTACs from initial discovery to clinical trials, highlighting advancements and challenges. Additionally, recent developments in fluorescent and photogenic PROTACs, used for real-time tracking of protein degradation, are presented, showcasing the evolving potential of PROTACs in targeted therapy.

Musculoskeletal disorders (MSDs) comprise diverse conditions affecting bones, joints, and muscles, leading to pain and loss of function, and are one of the most prevalent and major global health concerns. One of the hallmarks of MSDs is DNA damage. Once accumulated in the cytoplasm, the damaged DNA is sensed by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, which triggers the induction of type I interferons and inflammatory cytokines. Thus, this pathway connects the musculoskeletal and immune systems. Inhibitors of cGAS or STING have shown promising therapeutic effects in the pre-clinical models of several MSDs. Systemic, chronic, low-grade inflammation (SCLGI) underlies the development and maintenance of many MSDs. Failure to resolve SCLGI has been hypothesized to play a critical role in the development of chronic diseases, suggesting that the successful resolution of SCLGI will result in the alleviation of their related symptomatology. The process of inflammation resolution is feasible by specialized pro-resolving mediators (SPMs), which are enzymatically generated from dietary essential polyunsaturated fatty acids (PUFAs). The supplementation of SPMs or their stable, small-molecule mimetics and receptor agonists has revealed beneficial effects in inflammation-related animal models, including arthropathies, osteoporosis, and muscle dystrophy, suggesting a translational potential in MSDs. In this review, we substantiate the hypothesis that the use of cGAS-STING signaling pathway inhibitors together with SCLG-resolving compounds may serve as a promising new therapeutic approach for MSDs.

As antibiotic-resistant bacteria continue to emerge frequently, bacterial infections have become a significant and pressing challenge to global public health. Innate immunity triggers the activation of host responses by sensing "non-self" components through various pattern recognition receptors (PRRs), serving as the first line of antibacterial defense. Stimulator of interferon genes (STING) is a PRR that binds with cyclic dinucleotides (CDN) to exert effects against bacteria, viruses, and cancer by inducing the production of type I interferon and inflammatory cytokines, and facilitating regulated cell death. Currently, drugs targeting the STING signaling pathway are predominantly applied in the fields of modulating host immune defense against cancer and viral infections, with relatively limited application in treating bacterial infections. Given the significant immunomodulatory functions of STING in the interaction between bacteria and hosts, this review summarizes the research progress on STING signaling pathways and their roles in bacterial infection, as well as the novel functions of STING modulators, aiming to offer insights for the development of antibacterial drugs.

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Acute kidney injury (AKI) is a critical clinical syndrome associated with both innate and adaptive immune responses and thus increases mortality. Nevertheless, specific therapeutics for AKI are scarce so far. Recent studies have revealed that knockout of STING alleviate AKI, suggesting that STING could be an attractive target for AKI therapy. SN-011, a promising STING inhibitor, has not been reported in studies of its anti-AKI activity. In this study, we sought to examine the effects of SN-011 on AKI and explore its underlying mechanism. Our findings indicate that SN-011 could modulate the NF-κB and MAPK pathways, suppress the expression of inflammatory factors, and decrease ROS release in the cisplatin-induced cell model. In addition, SN-011 blocked the nuclear translocation of NF-κB p65, further mitigating the inflammatory response. In vivo, SN-011 enhanced survival rates and alleviated renal dysfunction. According to gene set enrichment analysis of sequencing data from mouse kidneys, we further confirm that SN-011 modulates the NF-κB and MAPK pathways. Our study suggests that SN-011 could be an attractive anti-inflammatory agent for further anti-AKI research.

Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered "undruggable" shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.

Molecules that are able to induce proximity between two proteins are finding ever increasing applications in chemical biology and drug discovery. The ability to introduce an electrophile and make such proximity inducers covalent can offer improved properties such as selectivity, potency, duration of action, and reduced molecular size. This concept has been heavily explored in the context of targeted degradation in particular for bivalent molecules, but recently, additional applications are reported in other contexts, as well as for monovalent molecular glues. This is a comprehensive review of reported covalent proximity inducers, aiming to identify common trends and current gaps in their discovery and application.

Alzheimer's disease (AD), the most common form of dementia, affects millions of people worldwide and its cause is very complicated. Besides the classical amyloid cascade hypothesis, oxidative stress, metal ion imbalance, cellular senescence and neuroinflammation are also considered crucial triggers of AD. Therefore, therapeutic strategies other than inhibiting Aβ deposition are very promising. As a crucial innate immune pathway, the abnormal activation of the cGAS-STING pathway in AD has attracted much attention and become a promising target for AD treatment. Here, we identify a highly conserved and stable G-quadruplex (G4) in the STING promoter region, and further verify its function in transcriptional inhibition of STING by using CRISPR technology to precisely target STING G4. Intriguingly, down-regulation of STING expression can alleviate cellular senescence and restore the Aβ phagocytic capacity of microglia. Our results highlight the compelling therapeutic potential of STING promoter G4 for regulation of the abnormal activation of the cGAS-STING pathway in AD. Different from the existing therapeutic strategies for AD, this work provides an alternative way of targeting the functional gene secondary structure, such as the STING promoter region, which may promote the design and synthesis of drug candidates for AD.

Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including VPOT64 and VPOT76, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, VPOT76 effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC50 of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that VPOT76 increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that VPOT76 inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that VPOT76 reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of VPOT76, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes VPOT76 as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC50 of 2.58 μM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.

Immune-inflammatory diseases are a class of conditions with high prevalence that severely impact the quality of life. Current treatment strategies include immunosuppressants, glucocorticoids, and monoclonal antibodies. However, these approaches have certain limitations, such as poor membrane permeability, immunogenicity, and the requirement for injection in large molecule drugs. Small molecule compounds, on the other hand, suffer from issues like poor selectivity, inability to inhibit non-enzymatic functions, and biological compensation. These factors constrain the effectiveness of current therapeutic strategies in immune-inflammatory diseases. As a novel small molecule drug development technology, proteolysis-targeting chimeras (PROTACs) regulate protein levels by inducing interactions between target proteins and E3 ubiquitin ligases, leading to the selective degradation of target proteins. This technology has already shown promising therapeutic effects in the treatment of immune-inflammatory diseases. This review aims to comprehensively summarize the application of PROTAC technology in the field of immune inflammation and provide insights into its potential in treating immune-inflammatory diseases.

Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis.

Bendamustine-rituximab (BR) therapy stands out as a promising alternative for elderly patients with diffuse large B-cell lymphoma (DLBCL), demonstrating notable efficacy when conventional regimens pose challenges. Despite its clinical success, the intricate mechanisms underlying BR therapy have remained elusive.

DLBCL cell lines were used to investigate the mechanism of BR therapy in vitro. RNA-seq and Western blot were used to explore the target pathways of BR therapy. STING was knocked out using Crispr-cas9 and inhibited using H-151 to investigate its role in BR therapy. Bulk RNA-seq and single-cell RNA-seq data from patients were analyzed to investigate the association between STING and pyroptosis pathways, validated using STING downregulated cells. Flow cytometry, transwell experiments and co-culture experiments were performed to investigate the inflammatory phenotype of DLBCL cells after BR treatment and its effect on T-cell recruitment and activation.

This study elucidates that BR elicits direct tumoricidal effects by promoting apoptosis and inducing cell cycle arrest. The synergistic impact with rituximab is further potentiated by complement addition, demonstrating the pivotal role of in vivo antibody-dependent cellular cytotoxicity. Moreover, our investigation reveals that, through a cGAS-STING-dependent pathway, prolonged exposure to BR induces pyroptosis in DLBCL cells. Activation of the cGAS-STING pathway by BR therapy triggers the release of inflammatory factors and upregulates major histocompatibility complex molecules, shaping an immunologically hot tumor microenvironment.

This unique dual influence not only directly targets DLBCL cells but also engages the patient's immune system, paving the way for innovative combination therapies. The study provides comprehensive insights into the multifaceted actions of BR in DLBCL, offering a foundation for refined and personalized treatment strategies in elderly patients.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.

The cGAS/STING signaling pathway is a crucial component of the innate immune system, playing significant roles in sensing cytosolic DNA, regulating cellular senescence, and contributing to oncogenesis. Recent advances have shed new lights into the molecular mechanisms governing pathway activation in multiple pathophysiological settings, the indispensable roles of cGAS/STING signaling in cellular senescence, and its context-dependent roles in cancer development and suppression. This review summarizes current knowledge related to the biology of cGAS/STING signaling pathway and its participations into senescence and oncogenesis. We further explore the clinical implications and therapeutic potential for cGAS/STING targeted therapies, and faced challenges in the field. With a focus on molecular mechanisms and emerging pharmacological targets, this review underscores the importance of future studies to harness the therapeutic potential of the cGAS/STING pathway in treating senescence-related disorders and cancer. Advanced understanding of the regulatory mechanisms of cGAS/STING signaling, along with the associated deregulations in diseases, combined with the development of new classes of cGAS/STING modulators, hold great promises for creating novel and effective therapeutic strategies. These advancements could address current treatment challenges and unlock the full potential of cGAS/STING in treating senescence-related disorders and oncogenesis.

Diabetes mellitus (DM) is one of the major causes of mortality worldwide, with inflammation being an important factor in its onset and development. This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway in mediating inflammatory responses. Furthermore, it comprehensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM, diabetic gastroenteropathy, diabetic cardiomyopathy, non-alcoholic fatty liver disease, and other complications. Additionally, the role of cGAS-STING in autonomic dysfunction and intestinal dysregulation, which can lead to digestive complications, has been discussed. Altogether, this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.

c-Met is an attractive therapeutic target in multiple tumors. Previous studies have discovered some effective proteolysis-targeting chimeras (PROTACs) able to degrade c-Met; however, the structure-activity relationship (SAR), degradation selectivity, and pharmacokinetic profiles of c-Met PROTACs have, to date, remained largely unknown. Herein, through extensive SAR studies on various warheads, linkers, and E3 ligase ligands, a novel potent c-Met PROTAC Met-DD4 was identified. Our results suggested that Met-DD4 could induce robust c-Met degradation with excellent selectivity (DC50 = 6.21 nM), substantially killing the c-Met-addicted cancer cells (IC50 = 4.37 nM). Furthermore, in vivo studies showed that Met-DD4 could achieve excellent oral bioavailability and c-Met degradation, strongly retarding tumor growth with minute organ toxicity. Overall, this study reveals that targeted degradation of c-Met is a promising strategy for the treatment of c-Met-addicted cancers and provides novel lead compounds for the clinical translation of c-Met PROTACs.

Stimuli-responsive low molecular weight hydrogel interventions for Biomedical challenges are a rapidly evolving paradigm in the bottom-up approach recently. Peptide-based self-assembled nano biomaterials present safer alternatives to their non-degradable counterparts as demanded for today's most urged clinical needs.Although a plethora of work has already been accomplished, programming hydrogelators with appropriate functionalities requires a better understanding as the impact of the macromolecular structure of the peptides and subsequently, their self-assembled nanostructures remain unidentified. Henceforth this review focuses on two aspects: Firstly, the underlying guidelines for building biomimetic strategies to tailor scaffolds leading to hydrogelation along with the role of non-covalent interactions that are the key components of various self-assembly processes. In the second section, it is aimed to bring together the recent achievements with designer assembly concerning their self-aggregation behaviour and applications mainly in the biomedical arena like drug delivery carrier design, antimicrobial, anti-inflammatory as well as wound healing materials. Furthermore, it is anticipated that this article will provide a conceptual demonstration of the different approaches taken towards the construction of these task-specific designer hydrogels. Finally, a collective effort among the material scientists is required to pave the path for the entrance of these intelligent materials into medicine from bench to bedside.

According to the mounting evidence in the literature, pro-inflammatory mediators/targets activate multiple signalling pathways to trigger illnesses that are ultimately responsible for acute pain, chronic inflammatory diseases, and several auto-immune disorders. Conventional drugs have been ruled out since proteolysis-targeting chimeras (PROTACs) are poised to overcome the limitations of traditional therapies. These heterobifunctional molecules help to degrade the targeted proteins of interest through ubiquitination. This review encompasses current and future aspects of PROTACs in inflammation-mediated and autoimmune targets. Different key points are highlighted and discussed, such as why PROTACs are preferred in this disease area, drawbacks and lessons learnt from the past, the role of linkers in establishing crucial degradation, in vitro findings, pharmacokinetics, in silico parameters, limitations of PROTACs in clinical settings, and future outcomes.

Over the past decade, it has become clear that the stimulator of interferon genes (STING) pathway is critical for a variety of immune responses. This endoplasmic reticulum-anchored adaptor protein has regulatory functions in host immunity across a spectrum of conditions, including infectious diseases, autoimmunity, neurobiology and cancer. In this Review, we outline the central importance of STING in immunological processes driven by expression of type I and III interferons, as well as inflammatory cytokines, and we look at therapeutic options for targeting STING. We also examine evidence that challenges the prevailing notion that STING activation is predominantly beneficial in combating cancer. Further exploration is imperative to discern whether STING activation in the tumor microenvironment confers true benefits or has detrimental effects. Research in this field is at a crossroads, as a clearer understanding of the nuanced functions of STING activation in cancer is required for the development of next-generation therapies.

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 μM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

With a growing number of covalent drugs securing FDA approval as successful therapies across various indications, particularly in the realm of cancer treatment, the covalent modulating strategy is undergoing a resurgence. The renewed interest in covalent bioactive compounds has captured significant attention from both the academic and biopharmaceutical industry sectors. Covalent chemistry presents several advantages over traditional noncovalent proximity-induced drugs, including heightened potency, reduced molecular size, and the ability to target "undruggable" entities. Within this perspective, we have compiled a comprehensive overview of current covalent modalities applied to proximity-induced molecules, delving into their advantages and drawbacks. Our aim is to stimulate more profound insights and ideas within the scientific community, guiding future research endeavors in this dynamic field.

While Stimulator-of-interferon genes (STING) is an innate immune adapter cruicial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.

Stimulator of interferon genes (STING), a homodimeric membrane receptor localized in the endoplasmic reticulum, plays a pivotal role in signaling innate immune responses. Inhibitors and proteolysis-targeting chimeras (PROTACs) targeting STING are promising compounds for addressing autoinflammatory and autoimmune disorders. In this study, we used a minimal covalent handle recently developed as the ligand portion of an E3 ligase. The engineered STING degrader with a low molecular weight compound covalently binds to STING and E3 ligase. Degrader 2 showed sustained STING degradation activity at lower concentrations (3 µM, 48 h, about 75 % degradation) compared to a reported STING PROTAC, SP23. This discovery holds significance for its potential in treating autoinflammatory and autoimmune diseases, offering promising avenues for developing more efficacious STING-targeted therapies.

Necroptosis is an important form of programmed cell death (PCD), which is mediated by a death receptor and independent of the caspase proteolytic enzyme. Mixed lineage kinase domain-like (MLKL) is the final effector of necroptosis, playing an irreplaceable role in the execution of necroptosis. However, the studies on MLKL inhibitors are in their infancy. Necrosulfonamide (NSA) is an early-discovered covalent MLKL inhibitor, possessing medium anti-necroptosis activity and a structure-activity relationship (SAR) not widely disclosed. In this study, with the covalent motif maintained, we aim to improve the activity by introducing the terminal fused heterocycles and meanwhile revealing the SAR on the part. As a result, compounds 9 and 14 showed the best activity (EC50 = 148.4 and 595.9 nM) against necroptosis among the analogues by covalently binding to MLKL. The SAR was also concluded to guide further structural optimization in this field.

Methylation of adenine N6 (m6A) is the most frequent RNA modification. On mRNA, it is catalyzed by the METTL3-14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types of blood cancers and solid tumors. Here, we disclose the first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein. For designing the PROTACs, we made use of the crystal structure of the complex of METTL3-14 with a potent and selective small-molecule inhibitor (called UZH2). The optimization of the linker started from a desfluoro precursor of UZH2 whose synthesis is more efficient than that of UZH2. The first nine PROTAC molecules featured PEG- or alkyl-based linkers, but only the latter showed cell penetration. With this information in hand, we synthesized 26 PROTACs based on UZH2 and alkyl linkers of different lengths and rigidity. The formation of the ternary complex was validated by a FRET-based biochemical assay and an in vitro ubiquitination assay. The PROTACs 14, 20, 22, 24, and 30, featuring different linker types and lengths, showed 50% or higher degradation of METTL3 and/or METTL14 measured by Western blot in MOLM-13 cells. They also showed substantial degradation on three other AML cell lines and prostate cancer cell line PC3.