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Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS(G12C) inhibitors

文献类型：期刊论文

作者Xiao, Xuanzheng1,2,3; Lai, Mengzhen2,3,4; Song, Zilan1,2,3; Geng, Meiyu2,3; Ding, Jian2,3; Xie, Hua2,3; Zhang, Ao1,2,3,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-03-05
卷号213页码:17
关键词KRAS Covalent inhibitor Pyridopyrimidinone Antiproliferative effect Scaffold hopping
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.113082
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRAS(G12C)), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS(G12C) inhibitor AMG510, a scaffold hopping strategy was conducted including a F-OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 mu M against KRAS(G12C) and cell growth inhibition of 0.79 mu M in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI-H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification. (C) 2020 Elsevier Masson SAS. All rights reserved.
资助项目Chinese NSF[81773565] ; Chinese NSF[81703327] ; Chinese NSF[81430080] ; Chinese NSF[81573452] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020366] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020226] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020374] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-11-021] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-017] ; Shanghai Jiao Tong University[AF1700037] ; Shanghai Jiao Tong University[WF220217002]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000629626600020
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/295313]  
专题新药研究国家重点实验室
通讯作者Xie, Hua; Zhang, Ao
作者单位1.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai Key Lab Mol Engn Chiral Drugs, Shanghai 200240, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
5.Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Minist Educ China, Zhengzhou 450001, Peoples R China
推荐引用方式
GB/T 7714		 Xiao, Xuanzheng,Lai, Mengzhen,Song, Zilan,et al. Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS(G12C) inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,213:17.
APA Xiao, Xuanzheng.,Lai, Mengzhen.,Song, Zilan.,Geng, Meiyu.,Ding, Jian.,...&Zhang, Ao.(2021).Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS(G12C) inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,213,17.
MLA Xiao, Xuanzheng,et al."Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRAS(G12C) inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 213(2021):17.

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来源：上海药物研究所

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