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

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

doi:10.1021/acsmedchemlett.8b00564

Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFR^{L858R/T790M/C797S}

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

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR^{L858R/T790M/C797S}. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFR^{L858R/T790M/C797S} with an IC₅₀ value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFR^{L858R/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.

Original language	English
Pages (from-to)	869-873
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00564
State	Published - 13 Jun 2019
Externally published	Yes

Keywords

C797S
EGFR
inhibitor
mutant

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10.1021/acsmedchemlett.8b00564

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title = "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.",

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author = "Qiannan Li and Tao Zhang and Shiliang Li and Linjiang Tong and Junyu Li and Zhicheng Su and Fang Feng and Deheng Sun and Yi Tong and Xia Wang and Zhenjiang Zhao and Lili Zhu and Jian Ding and Honglin Li and Hua Xie and Yufang Xu",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = jun,

day = "13",

doi = "10.1021/acsmedchemlett.8b00564",

language = "英语",

volume = "10",

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T1 - Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

AU - Li, Qiannan

AU - Zhang, Tao

AU - Li, Shiliang

AU - Tong, Linjiang

AU - Li, Junyu

AU - Su, Zhicheng

AU - Feng, Fang

AU - Sun, Deheng

AU - Tong, Yi

AU - Wang, Xia

AU - Zhao, Zhenjiang

AU - Zhu, Lili

AU - Ding, Jian

AU - Li, Honglin

AU - Xie, Hua

AU - Xu, Yufang

PY - 2019/6/13

Y1 - 2019/6/13

N2 - 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.

AB - 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.

KW - C797S

KW - EGFR

KW - inhibitor

KW - mutant

UR - https://www.scopus.com/pages/publications/85066492919

U2 - 10.1021/acsmedchemlett.8b00564

DO - 10.1021/acsmedchemlett.8b00564

M3 - 文章

AN - SCOPUS:85066492919

SN - 1948-5875

VL - 10

SP - 869

EP - 873

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 6

ER -

Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFR^{L858R/T790M/C797S}

Abstract

Keywords

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