2. Academic Validation
  3. Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

  • Bioorg Med Chem Lett. 2015 Oct 15;25(20):4557-61. doi: 10.1016/j.bmcl.2015.08.060.
Zhouling Xie 1,  Youli Zhou 1,  Wei Zhao 2,  He Jiao 1,  Yu Chen 1,  Yong Yang 2,  Zhiyu Li 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhiyuli@cpu.edu.cn.
PMID: 26342868 DOI: 10.1016/j.bmcl.2015.08.060
Abstract

A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 Enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong PARP-1 inhibitory activity (IC50=3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells (CC50=25.8 μM) and the BRCA1-deficient MDA-MB-436 cells (CC50=5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.

Keywords

BRCA1/2-deficient; DNA damage; Inhibitor; Molecular docking; Poly ADP-ribose polymerase-1 (PARP-1).

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