2. Academic Validation
  3. Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs)

Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs)

  • J Med Chem. 2022 Jul 14;65(13):9312-9327. doi: 10.1021/acs.jmedchem.2c00604.
Xue Yuan 1,  Yong Chen 1,  Minghai Tang 1,  Yuhan Wei 1,  Mingsong Shi 1,  Yingxue Yang 1,  Yanting Zhou 1,  Tao Yang 1,  Jiang Liu 1,  Kongjun Liu 1,  Dexin Deng 1,  Chufeng Zhang 1,  Lijuan Chen 1 2
Affiliations

Affiliations

  • 1 Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
PMID: 35709396 DOI: 10.1021/acs.jmedchem.2c00604
Abstract

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of a series of RIPK2 inhibitors derived from an FLT3 Inhibitor, CHMFL-FLT3-165. Compound 10w was identified to possess an IC50 value of 0.6 nM for RIPK2 and greater than 50,000-fold selectivity over its family homologous kinase RIPK1 (IC50 > 30 μM). It exhibited high kinase selectivity and inhibited RIPK2 to prevent NOD-induced cytokine production following muramyl dipeptide (MDP) stimulation. In an acute colitis model, compound 10w exerted better therapeutic effects than the JAK Inhibitor filgotinib and the RIPK2 Inhibitor WEHI-345. These robust results of in vitro and in vivo pharmacodynamic experiments demonstrate that RIPK2 as a therapeutic target shows potential abilities for the treatment of inflammatory bowel diseases.

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