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

Abstract

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.

• Authors: Gregory D Ferguson, Mercedes Delgado, Veronique Plantevin-Krenitsky, Kristen Jensen-Pergakes, R J Bates, Sanaa Torres, Maria Celeridad, Heather Brown, Kelven Burnett, Lisa Nadolny, Lida Tehrani, Garrick Packard, Barbra Pagarigan, Jason Haelewyn, Trish Nguyen, Li Xu, Yang Tang, Matthew Hickman, Frans Baculi, Steven Pierce, Keiji Miyazawa, Pilgrim Jackson, Philip Chamberlain, Laurie LeBrun, Weilin Xie, Brydon Bennett, Kate Blease
• Journal: PloS one (PLoS One) Vol. 11 Issue 1 Pg. e0145705 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26756335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CC-509
• Indazoles
• Intracellular Signaling Peptides and Proteins
• Pyridines
• Receptors, Fc
• Triazoles
• Collagen
• Protein-Tyrosine Kinases
• Vascular Endothelial Growth Factor Receptor-2
• JAK2 protein, human
• Janus Kinase 2
• SYK protein, human
• Syk Kinase
• Syk protein, rat

Topics

• Animals
• Arthritis, Experimental (drug therapy, 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)
• Indazoles (chemistry)
• Inflammation (drug therapy, physiopathology)
• Inhibitory Concentration 50
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Janus Kinase 2 (antagonists & inhibitors)
• Male
• Neutropenia (drug therapy)
• Neutrophils (cytology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyridines (chemistry)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley
• Receptors, Fc (chemistry)
• Skin (pathology)
• Syk Kinase
• Triazoles (chemistry)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)