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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 EGFRL858R/T790M/C797S.

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 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 o ...[more]

PMID: 31223440

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