Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs)

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 <b>10w</b> 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 <b>10w</b> 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.