ABSTRACT
Memory T cells possess functional differences from naïve T cells that powerfully contribute to the efficiency of secondary immune responses. These abilities are imprinted during the primary response, linked to the acquisition of novel patterns of gene expression. Underlying this are alterations at the chromatin level (epigenetic modifications) that regulate constitutive and inducible gene transcription. T cell epigenetic memory can persist long-term, contributing to long-lasting immunity after infection or vaccination. However, acquired epigenetic states can also hinder effective tumor immunity or contribute to autoimmunity. The growing understanding of epigenetic gene regulation as it relates to both the stability and malleability of T cell memory may offer the potential to selectively modify T cell memory in disease by targeting epigenetic mechanisms.
Subject(s)
Epigenesis, Genetic , Immunologic Memory , T-Lymphocytes , Chromatin/immunology , Epigenesis, Genetic/immunology , Gene Expression Regulation , Humans , Immunologic Memory/genetics , T-Lymphocytes/immunologyABSTRACT
Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 µM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).
Subject(s)
Enzyme Inhibitors/chemistry , Histone Demethylases/antagonists & inhibitors , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Pyridines/chemistry , Amination , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Histone Demethylases/chemistry , Histone Demethylases/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Models, Molecular , Pyridines/pharmacokinetics , Pyridines/pharmacologyABSTRACT
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Demethylases/antagonists & inhibitors , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Histone Demethylases/chemistry , Histone Demethylases/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Models, Molecular , Molecular Docking Simulation , Pyrimidinones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Isoxazoles/chemical synthesis , Nerve Tissue Proteins/antagonists & inhibitors , Quinolines/chemical synthesis , Animals , Binding Sites , Crystallography, X-Ray , Guinea Pigs , Heterocyclic Compounds, 4 or More Rings/metabolism , Inflammation/drug therapy , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mice , Models, Molecular , Protein Binding/drug effects , Quinolines/chemistry , Quinolines/pharmacology , RatsABSTRACT
OBJECTIVE: To characterize chronic murine pristane-induced arthritis (PIA) with regard to the response to antirheumatic agents, expression levels of proinflammatory cytokines, and immunopathologic features. METHODS: Male DBA/1 mice were injected intraperitoneally with pristane oil to induce a chronic polyarthritis, which was monitored by visual scoring. Serum antibody and splenocyte responses to a panel of putative joint-derived autoantigens were measured. Whole paws were evaluated postmortem for changes in the levels of proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-6 by enzyme-linked immunosorbent assay, and standard histopathology techniques were used to determine joint structural changes. Therapeutic studies were performed for up to 8 weeks of dosing with prednisolone, methotrexate, 3 nonsteroidal antiinflammatory drugs (celecoxib, diclofenac, and indomethacin), a p38 MAPK inhibitor, SB242235, and human soluble TNF receptor (sTNFR; etanercept) and murine sTNFR fusion proteins. RESULTS: Antibody and cellular responses to the putative joint autoantigens revealed a broad extent of autoimmunity in PIA. TNFalpha, IL-1beta, and IL-6 were all persistently up-regulated in PIA joints. Prednisolone, methotrexate, celecoxib, indomethacin, and SB242235 all significantly reduced the arthritis scores. Etanercept was ineffective in reducing the arthritis scores, whereas murine sTNFR produced a significant, but nonsustained, benefit. Only prednisolone significantly reduced the expression of TNFalpha, IL-1beta, and IL-6 in the joints. Prednisolone and methotrexate demonstrated the most effective joint protection. CONCLUSION: We have markedly extended the characterization of PIA as a murine model of chronic inflammatory arthritis by demonstrating cellular and humoral autoantigenicity, elevation of clinically precedented joint cytokines, and variation in the response to several antirheumatic therapies. PIA offers significant potential for the long-term study of immunopathologic mechanisms and novel therapies in rheumatoid arthritis.
