4.8 Article

A Small-Molecule Protein-Protein Interaction Inhibitor of PARP1 That Targets Its BRCT Domain

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

  1. National Council [CBRG/0038/2013]
  2. Ministry of Education [MOE2012-T2-1-116, MOE2012-T2-2-051]
  3. KIST [2Z04070/2E24860-2E25192]

向作者/读者索取更多资源

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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