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.

受体相互作用蛋白激酶1（Receptor-interacting protein kinase 1, RIPK1）是细胞坏死性凋亡的关键调控因子，被视为坏死性凋亡相关适应症的重要治疗靶点。本研究报道了一系列共晶型5-取代吲哚-3-甲酰胺衍生物的结构优化与构效关系研究。优选化合物10b对RIPK1展现出纳摩尔级的半最大抑制浓度（IC50），并具有良好的激酶选择性。基于其共晶结构，10b可同时占据RIPK1的变构口袋与ATP结合口袋，成为一种强效的RIPK1双模式抑制剂。体外实验中，10b可有效保护细胞免受坏死性凋亡损伤。化合物10b在肿瘤坏死因子α（TNFα）诱导的全身炎症反应综合征（SIRS）模型与咪喹莫特（IMQ）诱导的银屑病模型中均展现出显著的保护作用，同时具备良好的药代动力学特性与较低的毒性。综上，10b是一款极具开发潜力的RIPK1靶向药物先导化合物，值得开展进一步研究。