New Potent RIPK2 Inhibitors as a Promising Therapeutic Avenue for Colitis Through the Blockade of NOD Inflammatory Pathways

Inflammatory bowel diseases (IBDs) are conditions characterized by chronic inflammation of the bowel. Receptor-interacting Ser/Thr protein kinase 2, a key mediator in nucleotide oligomerization domain (NOD)-like receptor (NLRs) 1 (NOD1) and NOD2 inflammatory pathways, has been shown to be involved in the development of these pathologies. Here, we report the development of a series of quinazolines as receptor-interacting serine/threonine protein kinase 2 (RIPK2) inhibitors most of which highly block the NOD1 pathway while others block both NOD pathways. Nine of our best compounds show high cellular engagement of RIPK2 and were rather selective against a panel of 38 kinases. Compound 18, a NOD1/NOD2 pathway inhibitor, along with compound 2, a selective NOD1 pathway inhibitor, displays acceptable ADMET properties and inhibition of key pro-inflammatory cytokines in a DSS-induced murine model of colitis. In this context, this study demonstrates the potential of NOD-RIPK2 inhibitors as a therapeutic solution for IBD.