ABSTRACT
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Subject(s)
Cyclohexanols/therapeutic use , Graft vs Host Disease/drug therapy , Immunologic Factors/therapeutic use , Protein Kinase C-theta/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Caco-2 Cells , Cell Proliferation/drug effects , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase C-delta/antagonists & inhibitors , Protein Kinase C-delta/metabolism , Protein Kinase C-theta/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effectsABSTRACT
Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.
Subject(s)
Indazoles/chemistry , Inflammation/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Triazoles/chemistry , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/physiopathology , Basophils/cytology , Cell Line , Collagen/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Edema/pathology , Eosinophils/cytology , Female , HEK293 Cells , Humans , Hypertension/drug therapy , Inflammation/physiopathology , Inhibitory Concentration 50 , Janus Kinase 2/antagonists & inhibitors , Male , Neutropenia/drug therapy , Neutrophils/cytology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Receptors, Fc/chemistry , Skin/pathology , Syk Kinase , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
