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

Fei Huang, Nadish Goyal, Katherine Sullivan, Kritika Hanamshet, Mikir Patel, Olga M. Mazina, Charles X. Wang, W. Frank An, James Spoonamore, Shailesh Metkar, Kyle A. Emmitte, Simon Cocklin, Tomasz Skorski, Alexander V. Mazin

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.

Original languageEnglish
Pages (from-to)4189-4199
Number of pages11
JournalNucleic Acids Research
Volume44
Issue number9
DOIs
StatePublished - May 19 2016

Keywords

  • Antineoplastic Agents/pharmacology
  • BRCA1 Protein/genetics
  • BRCA2 Protein/genetics
  • Cell Line, Tumor
  • Cell Survival/drug effects
  • Cisplatin/pharmacology
  • DNA Damage
  • Drug Screening Assays, Antitumor
  • Gene Knockdown Techniques
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Protein Binding
  • Rad52 DNA Repair and Recombination Protein/antagonists & inhibitors

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