2. Academic Validation
  3. Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

  • Nucleic Acids Res. 2016 May 19;44(9):4189-99. doi: 10.1093/nar/gkw087.
Fei Huang 1,  Nadish Goyal 1,  Katherine Sullivan 2,  Kritika Hanamshet 1,  Mikir Patel 1,  Olga M Mazina 1,  Charles X Wang 1,  W Frank An 3,  James Spoonamore 3,  Shailesh Metkar 3,  Kyle A Emmitte 4,  Simon Cocklin 1,  Tomasz Skorski 2,  Alexander V Mazin 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
  • 2 Department of Microbiology and Immunology, and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 10140, USA.
  • 3 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 4 Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 5 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA Alexander.Mazin@DrexelMed.edu.
PMID: 26873923 DOI: 10.1093/nar/gkw087
Abstract

RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast Cancer and ovarian Cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for Cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1- and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel Cancer therapy and as a probe to study mechanisms of DNA repair.

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