ml8b00564_si_002.pdb (396.09 kB)

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

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posted on 28.05.2019, 21:46 by 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
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.