Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine790→ methionine790 mutant

Shilin Xu; Lianwen Zhang; Shaohua Chang; Jinfeng Luo; Xiaoyun Lu; Zhengchao Tu; Yingxue Liu; Zhang zhang; Yong Xu; Xiaomei Ren; Ke Ding

doi:10.1039/C2MD20078C

Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine⁷⁹⁰→ methionine⁷⁹⁰ mutant†

Shilin Xu,^ac Lianwen Zhang,^bc Shaohua Chang,^ac Jinfeng Luo,^a Xiaoyun Lu,^a Zhengchao Tu,^a Yingxue Liu,^a Zhang zhang,^a Yong Xu,^a Xiaomei Ren^a and Ke Ding*^a

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* Corresponding authors

^a Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China
E-mail: ding_ke@gibh.ac.cn
Fax: +86-20-32015299
Tel: +86-20-32015276

^b School of Life Science, University of Science and Technology of China, # 96 Jinzhai Road, Hefei 230026, China

^c Graduate School of Chinese Academy of Sciences, # 19 Yuquan Road, Beijing 100049, China

Abstract

A series of 5,8-dioxo-pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized as new inhibitors against wild-type EGFR and a panel of mutants, including the clinical resistance related T790M mutants. One of the most potent compounds 2l inhibited all forms of EGFR evaluated with low nM IC₅₀ values. It also strongly suppressed the proliferation of H1975 and HCC827 non-small cell lung cancer cells with IC₅₀ values of 69 and 71 nM, respectively.

MedChemComm

Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine⁷⁹⁰→ methionine⁷⁹⁰ mutant†

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Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine⁷⁹⁰→ methionine⁷⁹⁰ mutant

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