2. Academic Validation
  3. Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

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

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.

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