Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

Hualin Zhang; Ruliang Xie; Hawaa Ai-Furas; Yupeng Li; Qingxia Wu; Jian Li; Fang Xu; Tianfeng Xu

doi:10.1021/acsmedchemlett.1c00645

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

ACS Med Chem Lett. 2022 Jan 14;13(2):278-283. doi: 10.1021/acsmedchemlett.1c00645. eCollection 2022 Feb 10.

Authors

Hualin Zhang^{1

2}, Ruliang Xie², Hawaa Ai-Furas³, Yupeng Li⁴, Qingxia Wu², Jian Li¹, Fang Xu³, Tianfeng Xu^{2

5

6}

Affiliations

¹ Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China.
² Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug De-velopment, Ministry of Education (MOE) of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
⁴ Masonic Cancer Center & Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
⁵ University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

Abstract

The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR^{Del19/T790M/C797S} mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC₅₀ of 8 nM. It also showed good antiproliferation activity (IC₅₀ = 0.02 μM) against Ba/F3-EGFR^{Del19/T790M/C797S} cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.