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

  • ACS Med Chem Lett. 2019 May 22;10(6):869-873. doi: 10.1021/acsmedchemlett.8b00564.
Qiannan Li  1 ,  Tao Zhang  2 ,  Shiliang Li  1 ,  Linjiang Tong  2 ,  Junyu Li  1 ,  Zhicheng Su  1 ,  Fang Feng  2 ,  Deheng Sun  1 ,  Yi Tong  1 ,  Xia Wang  1 ,  Zhenjiang Zhao  1 ,  Lili Zhu  1 ,  Jian Ding  2 ,  Honglin Li  1 ,  Hua Xie  2 ,  Yufang Xu  1
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.
PMID: 31223440 DOI: 10.1021/acsmedchemlett.8b00564
Abstract

In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFRL858R/T790M/C797S. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFRL858R/T790M/C797S with an IC50 value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFRL858R/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.