期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 54, 期 8, 页码 2515-2519出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201410678
关键词
cancer; inhibitors; microarrays; PARP1; protein-protein interactions
资金
- National Council [CBRG/0038/2013]
- Ministry of Education [MOE2012-T2-1-116, MOE2012-T2-2-051]
- KIST [2Z04070/2E24860-2E25192]
Poly(ADP-ribose)polymerase-1 (PARP1) is a BRCT-containing enzyme (BRCT=BRCA1 C-terminus) mainly involved in DNA repair and damage response and a validated target for cancer treatment. Small-molecule inhibitors that target the PARP1 catalytic domain have been actively pursued as anticancer drugs, but are potentially problematic owing to a lack of selectivity. Compounds that are capable of disrupting protein-protein interactions of PARP1 provide an alternative by inhibiting its activities with improved selectivity profiles. Herein, by establishing a high-throughput microplate-based assay suitable for screening potential PPI inhibitors of the PARP1 BRCT domain, we have discovered that (+/-)-gossypol, a natural product with a number of known biological activities, possesses novel PARP1 inhibitory activity both invitro and in cancer cells and presumably acts through disruption of protein-protein interactions. As the first known cell-permeable small-molecule PPI inhibitor of PAPR1, we further established that (-)-gossypol was likely the causative agent of PARP1 inhibition by promoting the formation of a 1:2 compound/PARP1 complex by reversible formation of a covalent imine linkage.
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