Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

doi:10.1016/j.ejmech.2017.12.060

	Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation
	Geng, Kaijun 2,5,6; Xia, Zongjun 1,2,4; Ji, Yinchun 4; Zhang, Ruisi (Ruthy)3; Sun, Deqiao 1,2,4; Ai, Jing2,4 ; Song, Zilan 5,6; Geng, Meiyu1,2,4 ; Zhang, Ao1,2,5,6
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-01-20
卷号	144 页码:386-397
关键词	ALK G1202R mutant Drug resistance 2,4-Diarylaminopyrimidine Resorcinol
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.12.060
文献子类	Article
英文摘要	To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diary-laminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. (C) 2017 Published by Elsevier Masson SAS.
资助项目	Chinese NSF[81703327] ; Chinese NSF[8170130127] ; Chinese NSF[81430080] ; International Cooperative Program[GJHZ1622 2060899] ; Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400]
WOS关键词	ANAPLASTIC LYMPHOMA KINASE ; CELL LUNG-CANCER ; BRIGATINIB AP26113 ; PRECLINICAL MODELS ; POTENT ; CRIZOTINIB ; CERITINIB ; ACYLATION ; FUSION ; GENE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000425198100030
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279950]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第一研究室
通讯作者	Ai, Jing; Song, Zilan
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.Shanghai Int Studies Univ Bilingual Sch, Grade 12,Class 1, Shanghai 200083, Peoples R China 4.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, State Key Lab Drug Res, SIMM, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, CAS Key Lab Receptor Res, SIMM, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Geng, Kaijun,Xia, Zongjun,Ji, Yinchun,et al. Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,144:386-397.
APA	Geng, Kaijun.,Xia, Zongjun.,Ji, Yinchun.,Zhang, Ruisi .,Sun, Deqiao.,...&Zhang, Ao.(2018).Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,144,386-397.
MLA	Geng, Kaijun,et al."Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 144(2018):386-397.