A small-molecule protein-protein interaction inhibitor of PARP1 that targets its BRCT domain

Zhenkun Na, Bo Peng, Shukie Ng, Sijun Pan, Jun Seok Lee, Han Ming Shen, Shao Q. Yao

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2515-2519
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number8
Publication statusPublished - 2015 Feb 16
Externally publishedYes


  • Cancer
  • Inhibitors
  • Microarrays
  • PARP1
  • Protein-protein interactions

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)


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