title: A small-molecule protein-protein interaction inhibitor of PARP1 that targets its BRCT domain.
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.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore) http://staff.science.nus.edu.sg/∼syao.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Na
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.forename: Shukie
authors.initials: S
authors.lastname: Ng
authors.forename: Sijun
authors.initials: S
authors.lastname: Pan
authors.forename: Jun-Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
mesh_terms: D020134:Catalytic Domain; D006072:Gossypol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D040081:Protein Array Analysis; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D013237:Stereoisomerism
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D006072:Gossypol
keywords: PARP1; cancer; inhibitors; microarrays; protein-protein interactions