• Autoimmune
• Covalent
• Interleukin-2–inducible T cell kinase
• Janus kinase 3
• Kinase

• Janus Kinase 3/antagonists & inhibitors
• Janus Kinase 3/metabolism
• Humans
• Animals
• Male
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/pharmacokinetics
• Protein Kinase Inhibitors/therapeutic use
• Female
• Rats
• Mice
• Adult
• Young Adult
• Middle Aged
• Colitis/drug therapy

• Biologics
• Janus kinase inhibitor
• Real-world
• Tofacitinib
• Ulcerative colitis

• Adult
• Female
• Humans
• Male
• Middle Aged
• Young Adult
• Asian People
• Colectomy
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/diagnosis
• Janus Kinase Inhibitors/therapeutic use
• Janus Kinase Inhibitors/adverse effects
• Piperidines/therapeutic use
• Piperidines/adverse effects
• Pyrimidines/therapeutic use
• Pyrimidines/adverse effects
• Recurrence
• Remission Induction/methods
• Retrospective Studies
• Treatment Outcome

• BIM
• bisindolyl
• fragment-based design
• indole
• kinase inhibition
• maleimide

• GOIPG/2017/2082 Irish Research Council

• Acalypha indica
• Docking
• Molecular mechanism
• Mouse tail model
• Psoriasis

• Chronic pruritus
• Janus kinase
• antagonists
• neurokinin 1 receptor
• transient receptor potential vanilloid 1, transient receptor potential ankyrin 1

• Humans
• Dermatitis, Atopic/drug therapy
• Calcineurin Inhibitors/therapeutic use
• Dermatologic Agents/therapeutic use
• Administration, Topical
• Emollients/therapeutic use
• Phosphodiesterase 4 Inhibitors/therapeutic use
• Janus Kinase Inhibitors/therapeutic use

JAK1 plays a significant role in the intracellular signaling by interacting with cytokine receptors in different types of cells and is linked to the pathogenesis of various cancers and in the pathology of the immune system. In this study, ligand-based pharmacophore modeling combined with virtual screening and molecular docking methods was incorporated to identify the potent and selective lead compounds for JAK1. Initially, the ligand-based pharmacophore models were generated using a set of 52 JAK1 inhibitors named C-2 methyl/hydroxyethyl imidazopyrrolopyridines derivatives. Twenty-seven pharmacophore models with five and six pharmacophore features were generated and validated using potency and selectivity validation methods. During potency validation, the Guner-Henry score was calculated to check the accuracy of the generated models, whereas in selectivity validation, the pharmacophore models that are capable of identifying selective JAK1 inhibitors were evaluated. Based on the validation results, the best pharmacophore models ADHRRR, DDHRRR, DDRRR, DPRRR, DHRRR, ADRRR, DDHRR, and ADPRR were selected and taken for virtual screening against the Maybridge, Asinex, Chemdiv, Enamine, Lifechemicals, and Zinc database to identify the new molecules with novel scaffold that can bind to JAK1. A total of 4,265 hits were identified from screening and checked for acceptable drug-like properties. A total of 2,856 hits were selected after ADME predictions and taken for Glide molecular docking to assess the accurate binding modes of the lead candidates. Ninety molecules were shortlisted based on binding energy and H-bond interactions with the important residues of JAK1. The docking results were authenticated by calculating binding free energy for protein–ligand complexes using the MM-GBSA calculation and induced fit docking methods. Subsequently, the cross-docking approach was carried out to recognize the selective JAK1 lead compounds. Finally, top five lead compounds that were potent and selective against JAK1 were selected and validated using molecular dynamics simulation. Besides, the density functional theory study was also carried out for the selected leads. Through various computational studies, we observed good potency and selectivity of these lead compounds when compared with the drug ruxolitinib. Compounds such as T5923555 and T5923531 were found to be the best and can be further validated using in vitro and in vivo methods.

• Department of Science and Technology, Ministry of Science and Technology, India
• National Research Foundation of Korea
• Chosun University

Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV-229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counter selection and challenge with the β-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantation) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS-CoV-2 and variants-of-concern (alpha, beta, gamma, delta) from HAEEC in either pre- or post exposure regimens at clinically relevant concentrations. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral concentrations of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence synergy modelling. Neither MB, nor MPA, nor POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.

• Drug synergy in vitro
• Human coronavirus drug screen at single cell resolution in arrayed format
• Human explant nasal and bronchial epithelial cells
• Mycophenolic acid
• Posaconazole
• Post-entry coronavirus inhibition
• Repurposing methylene blue
• SARS-CoV-2 variants of concern

• chemical drug
• pathogenesis
• pathologic
• rheumatoid arthritis

• JAK1 inhibitor
• mouse CIA
• rat-AIA model
• rheumatoid arthritis

• Longwood Biopharma, Shanghai, China

Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of much debate. JAK3 has been proposed as an ideal target due to its expression being largely restricted to the immune system and its requirement for signalling by cytokine receptors using the common γ-chain. Unlike other JAKs, JAK3 possesses a cysteine in its ATP binding pocket and this has allowed the design of isoform selective covalent JAK3 inhibitors targeting this residue. We report here that mutating this cysteine to serine does not prevent JAK3 catalytic activity but does greatly increase the IC50 for covalent JAK3 inhibitors. Mice with a Cys905Ser knockin mutation in the endogenous JAK3 gene are viable and show no apparent welfare issues. Cells from these mice show normal STAT phosphorylation in response to JAK3 dependent cytokines but are resistant to the effects of covalent JAK3 inhibitors. These mice therefore provide a chemical-genetic model to study JAK3 function.

• Oxidation
• Pigment
• Sod
• Staphylococcus aureus
• crtM

• Anti-Bacterial Agents/pharmacology
• Bacterial Proteins/genetics
• Farnesyl-Diphosphate Farnesyltransferase/genetics
• Gene Expression Regulation, Bacterial/drug effects
• Pigmentation/drug effects
• Staphylococcus aureus/drug effects
• Superoxide Dismutase/genetics
• Virulence/drug effects

Staphylococcus aureus is the most important pathogenic bacteria in humans. As the resistance of S. aureus to existing antibiotics is increasing, there is an urgent need for new anti-infective drugs. S. aureus biofilms cause persistent infections and resist complete eradication with antibiotic therapy. The present study investigated the inhibitory effect of the novel small-molecule ZY-214-4 (C₁₉H₁₁BrNO₄) on S. aureus biofilm formation. At a subinhibitory concentration (4 μg/ml), ZY-214-4 had no effect on the growth of S. aureus strains and also showed no cytotoxicity in human normal bronchial epithelial cells (Bease-2B). The results of a semi-quantitative biofilm test showed that ZY-214-4 prevented S. aureus biofilm formation, which was confirmed by scanning electron microscopy and confocal laser scanning microscopy. ZY-214-4 significantly suppressed the production of polysaccharide intercellular adhesion and prevented cell aggregation, and also inhibited the mRNA expression of icaA and other biofilm-related genes (eno, clfA/B, fnbB, fib, ebpS, psmα, and psmβ) in clinical S. aureus isolates. Thus, at a subinhibitory concentration, ZY-214-4 inhibits biofilm formation by preventing cell aggregation, highlighting its clinical potential for preventing or treating S. aureus infections.

• Staphylococcus aureus
• biofilm
• cell aggregation
• icaA
• small-molecule compound

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8⁺ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8⁺ T cell proliferation as well as the number of KLRG⁺ effector and CD44^hiCD62L^lo effector memory CD8⁺ T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.

• CD8+ T cell
• JAK-STAT signaling pathway
• cytokines
• non-obese diabetic mouse
• type 1 diabetes mellitus

• Activation mutations
• Anticancer peptides
• Immunotherapeutics
• JAK3 inhibition
• Kinase isoform selectivity
• Peptide-based adjunct drugs

• Autoimmune disorder
• Docking
• Janus kinase 1
• Janus kinase 3
• Pharmacophore
• Prime MM/GBSA

• Biological therapy
• Disease-modifying antirheumatic drugs
• Inflammation
• Ligands
• Rheumatoid arthritis

Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine. A surprisingly large fraction of modified sites, across the three modifications, would be buried in native protein structure. Furthermore, modified cysteines are (on average) closer to lysine ubiquitinations than are unmodified cysteines, indicating that cysteine redox biology could be associated with protein degradation and degron recognition.

• Autoimmune disorders
• Docking
• Dual inhibitor
• Janus kinase-3 (JAK3)
• Phosphoinositide-3-kinase
• Rheumatoid arthritis
• e-pharmacophore

• Chemical probes
• Covalent inhibitors
• Covalent-reversible inhibitors
• Inflammation
• Isoform selectivity
• Janus kinase 3

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed.

• Animals
• Arthritis, Experimental/drug therapy
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/metabolism
• Dose-Response Relationship, Drug
• Drug Monitoring/methods
• Humans
• Isoenzymes
• Janus Kinase 1/antagonists & inhibitors
• Janus Kinase 1/chemistry
• Janus Kinase 1/metabolism
• Janus Kinase 3/antagonists & inhibitors
• Janus Kinase 3/chemistry
• Janus Kinase 3/metabolism
• Monitoring, Immunologic/methods
• Piperidines/pharmacology
• Protein Kinase Inhibitors/pharmacology
• Pyrimidines/pharmacology
• Pyrroles/pharmacology
• Rats

• JAK
• Janus kinase
• Tofacitinib
• Transplantation

• auto-immune disorders
• e-pharmacophore
• janus Kinase-3 (JAK3)
• multi-targeted
• spleen tyrosine kinase (Syk)

Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.

•

Identification and characterization of novel covalent reversible JAK3 inhibitors

• JAK3
• Janus kinases
• chemical probe
• covalent reversible inhibitor
• kinome selectivity

• JAK inhibitor
• Janus kinase (JAK)
• leukemia
• oncogene
• signal transduction
• tyrosine-protein kinase (tyrosine kinase)

• JAK
• JAK family selectivity
• JAK1
• JAK2
• JAK3
• Myeloproliferative disorders
• Myeloproliferative neoplasms
• TYK2

Tyrosine kinase 2 (TYK2) is a member of the Janus family of non-receptor tyrosine kinases involved in cytokine signaling. TYK2 deficiency is associated with increased susceptibility to mycobacterial and viral infections, hyper IgE syndrome as well as with allergic asthma. However the precise role of TYK2 in oncogenesis and tumor progression is not clear yet. Tyk2-deficient mice are prone to develop tumors because they lack efficient cytotoxic CD8⁺ T-cell antitumor responses as a result of deficient Type I interferon signaling. However, as TYK2 functions downstream of growth factor receptors that are often hyperactivated in cancer, inhibiting TYK2 might also have beneficial effects for cancer treatment.

• JAK-STAT signalling
• TYK2
• cancer
• cytokines
• lung cancer
• tumor therapy

• Arthritis, Rheumatoid/drug therapy
• Humans
• Immunosuppressive Agents/pharmacology
• Janus Kinases/antagonists & inhibitors
• Molecular Targeted Therapy
• Protein Kinase Inhibitors/pharmacology
• Signal Transduction/drug effects
• Small Molecule Libraries/pharmacology