title: Discovery of cell-permeable inhibitors that target the BRCT domain of BRCA1 protein by using a small-molecule microarray.
abstract: BRCTs are phosphoserine-binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain-containing, tumor-suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50% of hereditary breast cancers. Cell-permeable, small-molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray-based platforms, we have discovered the first cell-permeable protein-protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)2 domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation-induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small-molecule inhibitor of poly-ADP-ribose polymerase) and Etoposide (a small-molecule inhibitor of topoisomerase II). Unlike previously reported peptide-based PPI inhibitors of BRCA1, our compounds are small-molecule-like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP-related pathways in DNA damage and repair response, and in cancer therapy.
authors: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore) http://staff.science.nus.edu.sg/∼syao.
authors: Zhenkun
authors: Z
authors: Na
authors: Sijun
authors: S
authors: Pan
authors: Mahesh
authors: M
authors: Uttamchandani
authors: Shao Q
authors: SQ
authors: Yao
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry*; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D006801:Humans; D011485:Protein Binding; D046888:Tissue Array Analysis
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins
keywords: cancer; inhibitors; phosphopeptide-binding domain; protein-protein interaction; small-molecule microarray