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- Title
A Small-Molecule Protein-Protein Interaction Inhibitor of PARP1 That Targets Its BRCT Domain.
- Authors
Na, Zhenkun; Peng, Bo; Ng, Shukie; Pan, Sijun; Lee, Jun-Seok; Shen, Han-Ming; Yao, Shao Q.
- Abstract
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 in vitro 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.
- Subjects
MOLECULAR biology; ORGANIC compounds; PENTOSES; DEOXYRIBOSE; NUCLEIC acids
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 8, p2545
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201410678