文献类型：期刊文献

英文题名：Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy

作者：Chen, Wenhua[1];Guo, Ne[2,4];Qi, Minghui[3];Dai, Haiying[1];Hong, Minghuang[3];Guan, Longfei[1];Huan, Xiajuan[2];Song, Shanshan[2];He, Jinxue[2];Wang, Yingqing[2];Xi, Yong[2];Yang, Xinying[2];Shen, Yanyan[2];Su, Yi[2];Sun, Yiming[2];Gao, Yinglei[2];Chen, Yi[2];Ding, Jian[2];Tang, Yun[1];Ren, Guobin[3];Miao, Zehong[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;[3]East China Univ Sci & Technol, Sch Pharm, Lab Pharmaceut Crystal Engn & Technol, Shanghai 200237, Peoples R China;[4]Univ Chinese Acad Sci, Beijing 100049, Peoples R China

年份：2017

卷号：138

起止页码：514

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000411297000041)】；

基金：Financial support of this research was provided by the National Natural Science Foundation of China (Grants 21672064, 8152200403 and 21372001), the "Shu Guang" project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation (Grant 14SG28), the Science and Technology Commission of Shanghai Municipality (No. 15431901200), and the Fundamental Research Funds for the Central Universities. We gratefully acknowledge their support.

语种：英文

外文关键词：Antitumor drug; BRCA1/2; PARP inhibitors; Molecular docking

摘要：Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARPI inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 13 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARPI-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors. (C) 2017 Elsevier Masson SAS. All rights reserved.