Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFRT790M/C797S Mutants

Shan Li; Tao Zhang; Su-Jie Zhu; Chong Lei; Mengzhen Lai; Lijie Peng; Linjiang Tong; Zilu Pang; Xiaoyun Lu; Jian Ding; Xiaomei Ren; Cai-Hong Yun; Hua Xie; Ke Ding

doi:10.1021/acsmedchemlett.1c00555

Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR^T790M/C797S Mutants

ACS Med Chem Lett. 2022 Jan 7;13(2):196-202. doi: 10.1021/acsmedchemlett.1c00555. eCollection 2022 Feb 10.

Authors

Shan Li¹, Tao Zhang², Su-Jie Zhu³, Chong Lei⁴, Mengzhen Lai², Lijie Peng¹, Linjiang Tong², Zilu Pang², Xiaoyun Lu¹, Jian Ding², Xiaomei Ren¹, Cai-Hong Yun⁵, Hua Xie^{2

6}, Ke Ding^{1

4}

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511436, China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
³ Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
⁴ State Key Laboratory of Bioorganic Chemistry and Natural Products, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
⁵ Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
⁶ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.

Abstract

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR^T790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFR^{L858R/T790M/C797S} and EGFR^{19Del/T790M/C797S} kinases with IC₅₀ values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFR^T790M/C797S mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR^T790M/C797S with a close derivative 18f was solved to provide insight on the inhibitor's binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.