文献类型：期刊文献

英文题名：Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor

作者：Qian, Hewen[1];Ding, Yuanqing[2,3,4,5];Deng, Xingyu[1,2,3,4,5];Huang, Weiwei[6];Li, Zhenzhen[2,3,4,5];Liu, Fengling[2,3,4,5];Zhang, Jie[2,3,4,5];Wang, Lihui[7];Liu, Junping[7];Yuan, Yaxia[8];Hou, Shurong[2,3,4,5];Chen, Xiabin[2,3,4,5];Ma, Lei[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Hangzhou Normal Univ, Sch Pharm, Hangzhou 311121, Zhejiang, Peoples R China;[3]Key Lab Elemene Class Anti Canc Chinese Med, Hangzhou, Zhejiang, Peoples R China;[4]Engn Lab Dev & Applicat Tradit Chinese Med, Hangzhou, Zhejiang, Peoples R China;[5]Hangzhou Normal Univ, Collaborat Innovat Ctr Tradit Chinese Med Zhejiang, Hangzhou 311121, Zhejiang, Peoples R China;[6]Hangzhou Matrix Biopharmaceut Co Ltd, Hangzhou 311121, Zhejiang, Peoples R China;[7]Hangzhou Normal Univ, Sch Med, Inst Ageing Res, Hangzhou 311121, Zhejiang, Peoples R China;[8]Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA

年份：2023

卷号：256

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;EI(收录号：20230099161);WOS:【SCI-EXPANDED(收录号:WOS:001000811500001)】；

基金：This work was supported by the National Natural Science Foundation of China (Grants 81973196) .

语种：英文

外文关键词：Idiopathic pulmonary fibrosis; c -Jun N-Terminal kinase; Synthesis-accessibility; Inhibitor; Pyrimidine-2; 4-diamine; Structure-activity relationship; Fragment-based drug design

摘要：Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c-Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis. Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.