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Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations br

文献类型：期刊论文

作者Chen, Hao7,8; Lai, Mengzhen5,6; Zhang, Tao6; Chen, Yuqing7,8; Tong, Linjiang6; Zhu, Sujie4; Zhou, Yang7,8; Ren, Xiaomei3; Ding, Jian2,6; Xie, Hua1,2,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-05-12
卷号65期号:9页码:6840-6858
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00168
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Lu, Xiaoyun(luxy2016@jnu.edu.cn) ; Ding, Ke(dingke@jnu.edu.cn)
英文摘要tertiary C797S mutation of epidermal growthfactor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need.Several classes of adenosine 5 '-triphosphate-competitive orallosteric EGFRT790M/C797Sinhibitors and degraders have beendeveloped, but none of them have received approval from theregulatory agencies. Herein, we report the structure-based design ofconformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenyl-aminopyrimidines as new EGFRT790M/C797Sinhibitors by using amacrocyclization strategy. Representative compound18jpotentlyinhibited EGFR19del/T790M/C797Sand EGFRL858R/T790M/C797Smutantswith IC50values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797Sand Ba/F3-EGFR19del/T790M/C797Scells withIC50values of 0.036 and 0.052 mu M, respectively, which is 10-20-fold more potent than brigatinib.18jalso potently inhibited theEGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50value of 0.644 mu M but was less potent for parentalBa/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance inNSCLC patients.
WOS关键词EGFR KINASE INHIBITORS ; BRIGATINIB AP26113 ; ACCURATE DOCKING ; C797S RESISTANCE ; T790M MUTATION ; DISCOVERY ; MUTANT ; POTENT ; OSIMERTINIB ; AZD9291
资助项目National Natural Science Foundation of China[22037003] ; National Natural Science Foundation of China[81922062] ; National Natural Science Foundation of China[81820108029] ; National Natural Science Foundation of China[81903638] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-003] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-004] ; Personalized Medicines.Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020112] ; Open Fund of Shenzhen Bay Laboratory[SZBL202108061004] ; State Key Laboratory of Bioorganic and Natural Products Chemistry ; Lingang Laboratory[LG202103-02-02]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000802633700028
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/301539]  
专题新药研究国家重点实验室
通讯作者Xie, Hua; Lu, Xiaoyun; Ding, Ke
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China
4.Qingdao Univ, Coll Med, Inst Translat Med, Qingdao 266021, Peoples R China
5.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Jinan Univ, Affiliated Hosp 1, Huaqiao Hosp, Guangzhou 510632, Peoples R China
8.Jinan Univ, Huaqiao Hosp, Int Cooperat Lab Tradit Chinese Med Modernizat &, Minist Educ MOE,Sch Pharm,Guangzhou City Key Lab, Guangzhou 510632, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Hao,Lai, Mengzhen,Zhang, Tao,et al. Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations br[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(9):6840-6858.
APA Chen, Hao.,Lai, Mengzhen.,Zhang, Tao.,Chen, Yuqing.,Tong, Linjiang.,...&Ding, Ke.(2022).Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations br.JOURNAL OF MEDICINAL CHEMISTRY,65(9),6840-6858.
MLA Chen, Hao,et al."Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations br".JOURNAL OF MEDICINAL CHEMISTRY 65.9(2022):6840-6858.

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来源：上海药物研究所

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