論文 - 詳細
| RRC ID | 64971 |
|---|---|
| 著者 | Ferguson GD, Delgado M, Plantevin-Krenitsky V, Jensen-Pergakes K, Bates RJ, 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. |
| タイトル | A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation. |
| ジャーナル | PLoS One |
| 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. |
| 巻・号 | 11(1) |
| ページ | e0145705 |
| 公開日 | 2016-1-1 |
| DOI | 10.1371/journal.pone.0145705 |
| PII | PONE-D-15-43616 |
| PMID | 26756335 |
| PMC | PMC4710522 |
| MeSH | Animals Arthritis, Experimental / drug therapy Arthritis, Experimental / 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* Inflammation / 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 |
| IF | 2.74 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MH7A(RCB1512) |