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2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant

文献类型：期刊论文

作者Hu, Xianglong3; Xun, Qiuju3; Zhang, Tao4; Zhu, Su-Jie2; Li, Qian3; Tong, Linjiang4; Lai, Mengzhen4; Huang, Tao3; Yun, Cai-Hong1; Xie, Hua4
刊名CHINESE CHEMICAL LETTERS
出版日期2020-05-01
卷号31期号:5页码:1281-1287
ISSN号1001-8417
关键词EGFR(C797S) mutant SARs 2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidine Clinical resistance Fourth-generation inhibitors
DOI10.1016/j.cclet.2019.09.044
通讯作者Yun, Cai-Hong(yunch@hsc.pku.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Ding, Ke(dingke@jnu.edu.cn) ; Lu, Xiaoyun(luxy2016@jnu.edu.cn)
英文摘要Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFR(C797S )inhibitors. One of the most potent compound 6i potently suppressed EGFR(L858R/T790M/C797S) kinase with an IC50 value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFR-(L858R/T790M/C797S) and EGER(19D/T790M/C797S) mutants with IC50 values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFR-(L858R/T790M/C797S) and EGER(19D/T790M/C797S) in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. (C) 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
WOS关键词T790M-MEDIATED RESISTANCE ; MUTATION ; OSIMERTINIB ; DISCOVERY ; AZD9291
资助项目National Natural Science Foundation of China[81922062] ; National Natural Science Foundation of China[81874285] ; National Natural Science Foundation of China[81673285] ; Guangdong International Science and Technology Cooperation Project[2018A050506043] ; Guangzhou City Key Laboratory of Precision Chemical Drug Development[201805010007] ; Institutes for Drug Discovery and Development of Chinese Academy of Science[CASIMM0120185006]
WOS研究方向Chemistry
语种英语
出版者ELSEVIER SCIENCE INC
WOS记录号WOS:000531056900050
源URL[http://119.78.100.183/handle/2S10ELR8/280305]  
专题新药研究国家重点实验室
通讯作者Yun, Cai-Hong; Xie, Hua; Ding, Ke; Lu, Xiaoyun
作者单位1.Peking Univ, Sch Basic Med Sci, Inst Syst Biomed, Dept Biochem & Biophys,Hlth Sci Ctr, Beijing 100191, Peoples R China
2.Qingdao Univ, Coll Med, Inst Translat Med, Qingdao 266021, Peoples R China
3.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat &, Chinese Minist Educ MOE, Guangzhou 510632, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Xianglong,Xun, Qiuju,Zhang, Tao,et al. 2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant[J]. CHINESE CHEMICAL LETTERS,2020,31(5):1281-1287.
APA Hu, Xianglong.,Xun, Qiuju.,Zhang, Tao.,Zhu, Su-Jie.,Li, Qian.,...&Lu, Xiaoyun.(2020).2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant.CHINESE CHEMICAL LETTERS,31(5),1281-1287.
MLA Hu, Xianglong,et al."2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant".CHINESE CHEMICAL LETTERS 31.5(2020):1281-1287.

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来源：上海药物研究所

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