Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

被引：37

作者：

Shen, Jiayi ^{[1
]}

Zhang, Tao ^{[2
]}

Zhu, Su-Jie ^{[3
]}

Sun, Min ^{[4
]}

Tong, Linjiang ^{[2
]}

Lai, Mengzhen ^{[2
]}

Zhang, Rong ^{[5
]}

Xu, Wei ^{[1
]}

Wu, Ruibo ^{[5
]}

Ding, Jian ^{[2
]}

Yun, Cai-Hong ^{[6
]}

Xie, Hua ^{[2
]}

Lu, Xiaoyun ^{[1
]}

Ding, Ke ^{[1
]}

机构：

[1] Jinan Univ, Sch Pharm, Guangzhou City Key Lab Precis Chem Drug Dev,Minis, Int Cooperat Lab Tradit Chinese Med Modernizat &, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China

[2] Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

[3] Qingdao Univ, Inst Translat Med, Coll Med, Qingdao 266021, Shandong, Peoples R China

[4] Jiangsu Aosaikang Pharmacceut Co Ltd, 699 Kejian Rd,Jiangsu Sci Pk, Nanjing 211112, Jiangsu, Peoples R China

[5] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China

[6] Peking Univ, Hlth Sci Ctr, Dept Biochem & Biophys, Inst Syst Biomed,Sch Basic Med Sci, Beijing 100191, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 15期

基金：

中国国家自然科学基金;

关键词：

LUNG-CANCER; EGFR INHIBITORS; RESISTANCE; GEFITINIB; OPTIMIZATION; DISCOVERY; MUTATIONS; AZD9291;

D O I：

10.1021/acs.jmedchem.9b00576

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Tertiary EGFRc797s mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR(L858R/T790M/C797S) inhibitors. A representative compound, 8r-B, exhibited an ICso of 27.5 nM against the EGFR(L858R/T790M/C797S) mutant, while being a significantly less potent for EGFRwr (IC50 > 1.0 NM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

引用

页码：7302 / 7308

页数：7

共 49 条

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SCIENTIFIC REPORTS, 2024, 14 (01):
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MOLECULAR DIVERSITY, 2024,
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