title: Protein-Protein Interaction Inhibitors of BRCA1 Discovered Using Small Molecule Microarrays.
abstract: Microarray screening technology has transformed the life sciences arena over the last decade. The platform is widely used in the area of mapping interaction networks, to molecular fingerprinting and small molecular inhibitor discovery. The technique has significantly impacted both basic and applied research. The microarray platform can likewise enable high-throughput screening and discovery of protein-protein interaction (PPI) inhibitors. Herein we demonstrate the application of microarray-guided PPI inhibitor discovery, using human BRCA1 as an example. Mutations in BRCA1 have been implicated in ~50 % of hereditary breast cancers. By targeting the (BRCT)2domain, we showed compound 15a and its prodrug 15b inhibited BRCA1 activities in tumor cells. Unlike previously reported peptide-based PPI inhibitors of BRCA1, the compounds identified could be directly administered to tumor cells, thus making them useful in targeting BRCA1/PARP-related pathways involved in DNA damage and repair response, for cancer therapy.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Na
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Sijun
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.|Defence Medical & Environmental Research Institute, DSO National Laboratories, Singapore, Singapore.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Uttamchandani
authors.affiliation: Department of Chemistry, Faculty of Science, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore. chmyaosq@nus.edu.sg.
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
mesh_terms: D017209:Apoptosis; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D002151:Calorimetry; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D046228:Microarray Analysis / Q000379:methods*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis*; D013194:Staining and Labeling
chemical_list: D019313:BRCA1 Protein; D010455:Peptides; D054852:Small Molecule Libraries; D053148:Caspase 3
keywords: Cancer; Phosphopeptide-binding domain; Phosphorylation; Protein–protein interaction inhibitor; Small molecule microarray