4WNM

SYK catalytic domain in complex with a potent triazolopyridine inhibitor

Summary for 4WNM

• Entry DOI: 10.2210/pdb4wnm/pdb
• Descriptor: Tyrosine-protein kinase SYK, N~3~-(tetrahydro-2H-pyran-4-yl)-N~6~-[5-(tetrahydro-2H-pyran-4-ylmethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1H-indazole-3,6-diamine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: syk catalytic domain in complex with a potent triazolopyridine based inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane : P43405
• Total number of polymer chains: 1
• Total formula weight: 35424.57

Authors

Jackson, P.J. (deposition date: 2014-10-13, release date: 2016-01-20, Last modification date: 2023-12-27)

Primary citation

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.
A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.
Plos One, 11:e0145705-e0145705, 2016

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.

PubMed: 26756335
DOI: 10.1371/journal.pone.0145705

Experimental method

X-RAY DIFFRACTION (2.5 Å)