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
收藏
页码：7302 / 7308
页数：7
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