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

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.