Ring closure strategy leads to potent RIPK3 inhibitors

Shuwei Wu; Chen Xu; Kaijiang Xia; Yu Lin; Sheng Tian; Haikuo Ma; Yuting Ji; Fang Zhu; Sudan He; Xiaohu Zhang

doi:10.1016/j.ejmech.2021.113327

Ring closure strategy leads to potent RIPK3 inhibitors

Eur J Med Chem. 2021 May 5:217:113327. doi: 10.1016/j.ejmech.2021.113327. Epub 2021 Mar 9.

Authors

Shuwei Wu¹, Chen Xu¹, Kaijiang Xia¹, Yu Lin¹, Sheng Tian¹, Haikuo Ma¹, Yuting Ji², Fang Zhu², Sudan He³, Xiaohu Zhang⁴

Affiliations

¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China.
² Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China.
³ Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China. Electronic address: hesudan2018@163.com.
⁴ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: xiaohuzhang@suda.edu.cn.

PMID: 33730678
DOI: 10.1016/j.ejmech.2021.113327

Abstract

Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC₅₀ = 0.42 μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (K_d = 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another necroptosis regulator RIPK1 (K_d = 6000 nM). Furthermore, compound 38 demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.

Keywords: Cell death; Inflammation; Kinase; Necroptosis; RIPK1; RIPK3.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Death / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hypothermia / drug therapy
Hypothermia / metabolism
Injections, Intravenous
Mice
Mice, Inbred C57BL
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Structure-Activity Relationship
Systemic Inflammatory Response Syndrome / drug therapy
Systemic Inflammatory Response Syndrome / metabolism
Tumor Necrosis Factor-alpha / administration & dosage
Tumor Necrosis Factor-alpha / pharmacology

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases