Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors

Shuwei Wu; Liben Xu; Xinhui Wang; Qing Yang; Jingrui Wang; Sudan He; Xiaohu Zhang

doi:10.1016/j.bmcl.2022.128968

Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors

Bioorg Med Chem Lett. 2022 Nov 1:75:128968. doi: 10.1016/j.bmcl.2022.128968. Epub 2022 Sep 2.

Authors

Shuwei Wu¹, Liben Xu¹, Xinhui Wang², Qing Yang¹, Jingrui Wang², Sudan He³, Xiaohu Zhang⁴

Affiliations

¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
² CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China.
³ CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: hesd@ism.pumc.edu.cn.
⁴ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: xiaohuzhang@suda.edu.cn.

PMID: 36058467
DOI: 10.1016/j.bmcl.2022.128968

Abstract

The NOD1/2 (nucleotide-binding oligomerization domain-containing protein 1/2) signaling pathways are involved in innate immune control and host defense. NOD dysfunction can result in a variety of autoimmune disorders. NOD-induced generation of inflammatory cytokines is mediated by receptor-interacting protein kinase 2 (RIPK2), which has been considered as a promising therapeutic target. Herein, we disclose the design, synthesis, and SAR study of a series of RIPK2 inhibitors. The lead compound 17 displayed a high affinity for RIPK2 (K_d = 5.9 nM) and was capable of inhibiting RIPK2 kinase function in an ADP-Glo assay. In vitro DMPK studies showed that compound 17 had good metabolic stability and no CYP inhibition. Compound 17 effectively suppressed inflammatory cytokine production in both cells and animal model.

Keywords: Autoimmune disorders; Inhibitor; Kinase; NOD; RIPK2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Diphosphate
Animals
Cytokines* / metabolism
Iohexol* / analogs & derivatives
Structure-Activity Relationship

Substances

Cytokines
compound 17
Iohexol
Adenosine Diphosphate