Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

Qiannan Li; Tao Zhang; Shiliang Li; Linjiang Tong; Junyu Li; Zhicheng Su; Fang Feng; Deheng Sun; Yi Tong; Xia Wang; Zhenjiang Zhao; Lili Zhu; Jian Ding; Honglin Li; Hua Xie; Yufang Xu

doi:10.1021/acsmedchemlett.8b00564

Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFR^{L858R/T790M/C797S}

ACS Med Chem Lett. 2019 May 22;10(6):869-873. doi: 10.1021/acsmedchemlett.8b00564. eCollection 2019 Jun 13.

Authors

Qiannan Li¹, Tao Zhang², Shiliang Li¹, Linjiang Tong², Junyu Li¹, Zhicheng Su¹, Fang Feng², Deheng Sun¹, Yi Tong¹, Xia Wang¹, Zhenjiang Zhao¹, Lili Zhu¹, Jian Ding², Honglin Li¹, Hua Xie², Yufang Xu¹

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR^{L858R/T790M/C797S}. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFR^{L858R/T790M/C797S} with an IC₅₀ value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFR^{L858R/T790M/C797S}-dependent cells. This series of compounds, which occupy both the ATP binding site and the allosteric site of the EGFR kinase, may serve as a basis for the development of fourth-generation EGFR inhibitors for L858R/T790M/C797S mutants.