Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs
文献类型：期刊论文
| 作者 | Geng, Kaijun1,2,3; Liu, Hongchun4 ; Song, Zilan2,3; Zhang, Chi2,3; Zhang, Minmin4; Yang, Hong4; Cao, Jingchen4; Geng, Meiyu1,4,5; Shen, Aijun4; Zhang, Ao1,2,3,5
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-05-25 |
| 卷号 | 152页码:76-86 |
| 关键词 | Heat shock protein 90 (Hsp90) Tyrosine kinase ALK Dual inhibitor Drug resistance Antiproliferative activity |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2018.04.019 |
| 文献子类 | Article |
| 英文摘要 | Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (173 vs 9.8 nM) and Hsp90 alpha (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALK(L1196M). Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AICT, and up-regulation of the chaperone protein Hsp70 in H3122 cells. (C) 2018 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | ANAPLASTIC LYMPHOMA KINASE ; CELL LUNG-CANCER ; CRIZOTINIB RESISTANCE ; CHAPERONE INHIBITORS ; BRIGATINIB AP26113 ; PRECLINICAL MODELS ; FUSION ONCOGENE ; POTENT ; DISCOVERY ; EML4-ALK |
| 资助项目 | Chinese NSF[81430080] ; Chinese NSF[81703327] ; Chinese NSF[81773565] ; Supporting grants from the International Cooperative Program of the Chinese Academy of Sciences[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000435048900007 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279741]  |
| 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 | Geng, Meiyu; Shen, Aijun; Zhang, Ao |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Geng, Kaijun,Liu, Hongchun,Song, Zilan,et al. Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,152:76-86. |
| APA | Geng, Kaijun.,Liu, Hongchun.,Song, Zilan.,Zhang, Chi.,Zhang, Minmin.,...&Zhang, Ao.(2018).Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,152,76-86. |
| MLA | Geng, Kaijun,et al."Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 152(2018):76-86. |
入库方式： OAI收割
来源：上海药物研究所
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