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

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

  • J Med Chem. 2024 Jan 11;67(1):754-773. doi: 10.1021/acs.jmedchem.3c02102.
Liting Zhang 1,  Yueshan Li 1 2,  Chenyu Tian 1,  Ruicheng Yang 1,  Yifei Wang 1,  Haixing Xu 1,  Qiucheng Zhu 1,  Shasha Chen 1,  Linli Li 3,  Shengyong Yang 1 2
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
PMID: 38159286 DOI: 10.1021/acs.jmedchem.3c02102
Abstract

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.

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