From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases

Receptor-interacting
protein kinase 1 (RIPK1) is a key regulator
of cellular necroptosis, which is considered as an important therapeutic
target for necroptosis-related indications. Herein, we report the
structural optimization and structure–activity relationship
investigations of a series of eutectic 5-substituted-indole-3-carboxamide
derivatives. The prioritized compound 10b exhibited low
nanomolar IC50 values against RIPK1 and showed good kinase
selectivity. Based on its eutectic structure, 10b occupied
both the allosteric and ATP binding pockets of RIPK1, making it a
potent dual-mode inhibitor of RIPK1. In vitro, 10b had a potent protective effect against necroptosis in
cells. Compound 10b also provided robust protection in
a TNFα-induced systemic inflammatory response syndrome (SIRS)
model and imiquimod (IMQ)-induced psoriasis model. It also showed
good pharmacokinetic properties and low toxicity. Overall, 10b is a promising lead compound for drug discovery targeting RIPK1
and warrants further study.