期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 145, 期 -, 页码 389-403出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.01.018
关键词
PARP1/2 inhibitor; Benzimidazole; 4,5,6,7-Tetrahydrothienopyridine; Co-crystal structure; Isothermal Titration Calorimetry
资金
- National Natural Science Foundation of China [21072205, 81422047]
- Chinese Academy of Sciences [CASIMM0120152003]
The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway. (C) 2018 Elsevier Masson SAS. All rights reserved.
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