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

Journal Article · · PLoS ONE
 [1];  [2];  [2];  [3];  [4];  [4];  [4];  [5];  [2];  [2];  [2];  [2];  [6];  [6];  [6];  [4];  [5];  [6];  [6];  [6] more »;  [7];  [6];  [6];  [6];  [4];  [4];  [5] « less
  1. Celgene Corporation, San Diego, CA (United States). Dept. of Inflammation Research; DOE/OSTI
  2. Celgene Corporation, San Diego, CA (United States). Dept. of Chemistry
  3. Pfizer Corporation, San Diego, CA (United States)
  4. Celgene Corporation, San Diego, CA (United States). Dept. of Inflammation Research
  5. Celgene Corporation, San Diego, CA (United States). Dept. of Pharmacology
  6. Celgene Corporation, San Diego, CA (United States). Dept. of Biochemistry
  7. Kissei Pharmaceutical Company, Nagano (Japan). Dept. of Corporate Planning and Strategy
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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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627777
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 1 Vol. 11; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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