Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation | |
Geng, Kaijun2,5,6; Xia, Zongjun1,2,4; Ji, Yinchun4; Zhang, Ruisi (Ruthy)3; Sun, Deqiao1,2,4; Ai, Jing2,4; Song, Zilan5,6; 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. |
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