Repurposing of clinical-stage FLT3 inhibitor HYML-122 as a potent RIPK2 inhibitor for the treatment of inflammatory bowel disease.

Nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD 1/2) are important cytoplasmic pattern recognition receptors that initiate host immune responses. Dysregulation of NOD signaling is highly associated with inflammatory bowel disease (IBD) and necessitate efficient treatment options. As a key mediator of NOD signals, receptor-interacting protein kinase 2 (RIPK2) was considered as a promising therapeutic target for IBD therapy. However, no approved RIPK2 inhibitors are currently available for clinical use. we screened our in-house compound library using a phenotype-based cell assay and found the compound HYML-122, which a known FLT3 inhibitor currently under clinical investigation, can effectively block the function of RIPK2 kinase and NOD-mediated NF-κB/MAPK activation in mouse cells. Furthermore, HYML-122 significantly inhibited the production of pro-inflammatory cytokines induced by muramyl dipeptide (MDP) in human peripheral blood mononuclear cells (hPBMCs) and MDP-induced peritonitis in mice. In addition, HYML-122 is highly enriched in the intestinal tract, and significantly improve Dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats and dextran sulfate sodium (DSS)-induced colitis in mice. In conclusion, this study presented HYML-122 is a promising RIPK2 inhibitor with potential for further drug development for the treatment of IBD.