Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs).
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| Abstract |
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of a series of RIPK2 inhibitors derived from an FLT3 inhibitor, CHMFL-FLT3-165. Compound 10w was identified to possess an IC50 value of 0.6 nM for RIPK2 and greater than 50,000-fold selectivity over its family homologous kinase RIPK1 (IC50 > 30 μM). It exhibited high kinase selectivity and inhibited RIPK2 to prevent NOD-induced cytokine production following muramyl dipeptide (MDP) stimulation. In an acute colitis model, compound 10w exerted better therapeutic effects than the JAK inhibitor filgotinib and the RIPK2 inhibitor WEHI-345. These robust results of in vitro and in vivo pharmacodynamic experiments demonstrate that RIPK2 as a therapeutic target shows potential abilities for the treatment of inflammatory bowel diseases.
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| Authors | Xue Yuan, Yong Chen, Minghai Tang, Yuhan Wei, Mingsong Shi, Yingxue Yang, Yanting Zhou, Tao Yang, Jiang Liu, Kongjun Liu, Dexin Deng, Chufeng Zhang, Lijuan Chen |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 13 Pg. 9312-9327 (07 14 2022) ISSN: 1520-4804 [Electronic] United States |
| PMID | 35709396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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