A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation

• Published in: PloS one 2016-01, Vol.11 (1), p.e0145705-e0145705
• Main Authors: Ferguson, Gregory D, Delgado, Mercedes, Plantevin-Krenitsky, Veronique, Jensen-Pergakes, Kristen, Bates, R J, Torres, Sanaa, Celeridad, Maria, Brown, Heather, Burnett, Kelven, Nadolny, Lisa, Tehrani, Lida, Packard, Garrick, Pagarigan, Barbra, Haelewyn, Jason, Nguyen, Trish, Xu, Li, Tang, Yang, Hickman, Matthew, Baculi, Frans, Pierce, Steven, Miyazawa, Keiji, Jackson, Pilgrim, Chamberlain, Philip, LeBrun, Laurie, Xie, Weilin, Bennett, Brydon, Blease, Kate
• Format: Article
• Language: English
• Subjects: Adapter proteins; Anaphylaxis; Animal models; Animals; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - physiopathology; Autoantibodies; Autoimmune diseases; BASIC BIOLOGICAL SCIENCES; Basophils - cytology; Bioavailability; Biochemistry; Cell activation; Cell Line; Chemistry; Clinical trials; Collagen; Collagen - chemistry; Crystallography, X-Ray; Cytokines; Disease; Dose-Response Relationship, Drug; Drug therapy; Edema; Edema - pathology; Enzyme inhibitors; Eosinophils - cytology; Fc receptors; Female; HEK293 Cells; Humans; Hypertension; Hypertension - drug therapy; Immune system; Immunology; Indazoles - chemistry; Inflammation; Inflammation - drug therapy; Inflammation - physiopathology; Inhibitors; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Joints (Anatomy); Kinases; Lupus; Male; Medical research; Neutropenia; Neutropenia - drug therapy; Neutrophils - cytology; Passive cutaneous anaphylaxis; Pathogenesis; Pharmaceutical industry; Pharmacology; Protein-tyrosine kinase receptors; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines - chemistry; RANTES; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors; Receptors, Fc - chemistry; Rheumatoid arthritis; Science & Technology - Other Topics; Signal transduction; Signaling; Skin; Skin - pathology; Spleen; Syk Kinase; Syk protein; Testing; Triazoles - chemistry; Tyrosine; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0145705

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.