Discovery of SHR2415, a Novel Pyrrole-Fused Urea Scaffold ERK1/2 Inhibitor

Xin Li; Ping Dong; Ting Zhang; Guodong Cai; Yang Chen; Huaide Dong; Fang Yang; Lei Zhang; Yuchang Mao; Jun Feng; Chang Bai; Feng He; Weikang Tao

doi:10.1021/acsmedchemlett.2c00029

Discovery of SHR2415, a Novel Pyrrole-Fused Urea Scaffold ERK1/2 Inhibitor

ACS Med Chem Lett. 2022 Apr 1;13(4):701-706. doi: 10.1021/acsmedchemlett.2c00029. eCollection 2022 Apr 14.

Authors

Xin Li¹, Ping Dong¹, Ting Zhang¹, Guodong Cai¹, Yang Chen¹, Huaide Dong¹, Fang Yang¹, Lei Zhang¹, Yuchang Mao¹, Jun Feng¹, Chang Bai¹, Feng He¹, Weikang Tao¹

Affiliation

¹ R&D Center, Shanghai Hengrui Pharmaceutical Co., LTD., 279 Wenjing Road, Shanghai 200245, China.

Abstract

ERK1/2 kinase is a key downstream node of the RAS-RAF-MEK-ERK signaling pathway. A highly potent and selective ERK1/2 inhibitor is a promising option for cancer treatment that will provide a potential solution for overcoming drug resistance. Herein we designed and synthesized a novel scaffold featuring a pyrrole-fused urea template. The lead compound, SHR2415, was shown to be a highly potent ERK1/2 inhibitor that exhibited high cell potency based on the Colo205 assay. In addition, SHR2415 displayed favorable PK profiles across species as well as robust in vivo efficacy in a mouse Colo205 xenograft model.