Download MendeleyA Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.
Ferguson, G.D., Delgado, M., Plantevin-Krenitsky, V., Jensen-Pergakes, K., Bates, R.J., Torres, S., Celeridad, M., Brown, H., Burnett, K., Nadolny, L., Tehrani, L., Packard, G., Pagarigan, B., Haelewyn, J., Nguyen, T., Xu, L., Tang, Y., Hickman, M., Baculi, F., Pierce, S., Miyazawa, K., Jackson, P., Chamberlain, P., LeBrun, L., Xie, W., Bennett, B., Blease, K.(2016) PLoS One 11: e0145705-e0145705
- PubMed: 26756335
- DOI: https://doi.org/10.1371/journal.pone.0145705
- Primary Citation of Related Structures:
4WNM - PubMed 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.
Organizational Affiliation:
Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
