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

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.

SUBMITTER: Li Q 

PROVIDER: S-EPMC6580378 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFR<sup>L858R/T790M/C797S</sup>.

Li Qiannan Q   Zhang Tao T   Li Shiliang S   Tong Linjiang L   Li Junyu J   Su Zhicheng Z   Feng Fang F   Sun Deheng D   Tong Yi Y   Wang Xia X   Zhao Zhenjiang Z   Zhu Lili L   Ding Jian J   Li Honglin H   Xie Hua H   Xu Yufang Y  

ACS medicinal chemistry letters 20190522 6

In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR<sup>L858R/T790M/C797S</sup>. One of the most promising compounds, <b>25g</b>, inhibited the enzymatic activity of EGFR<sup>L858R/T790M/C797S</sup> with an IC<sub>50</sub> value of 2.2 nM. Cell proliferation assays showed that <b>25g</b> effectively and selectively inhibited the growth of EGFR<sup>L858R/T790M/C797S</sup>-dependent cells. This series o  ...[more]

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