A Small-Molecule Protein-Protein Interaction Inhibitor of PARP1 That Targets Its BRCT Domain
- A Small-Molecule Protein-Protein Interaction Inhibitor of PARP1 That Targets Its BRCT Domain
- Zhenkun Na; Bo Peng; Shukie Ng; Sijun Pan; 이준석; Han Ming Shen; Shao Q. Yao
- protein protein interaction; mass spectrometry
- Issue Date
- Angewandte Chemie international edition
- VOL 127, 2545-2549
- 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 microplatebased 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.
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