Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

  • Bioorg Med Chem Lett. 2017 Jul 15;27(14):3096-3100. doi: 10.1016/j.bmcl.2017.05.039.
Ambber Ward  1 ,  Lilong Dong  2 ,  Jonathan M Harris  3 ,  Kum Kum Khanna  4 ,  Fares Al-Ejeh  1 ,  David P Fairlie  5 ,  Adrian P Wiegmans  6 ,  Ligong Liu  7
Affiliations
  • 1. Personalised Medicine, QIMR Berghofer Medical Research Institute, Herston Rd, Herston, Brisbane, Queensland, Australia.
  • 2. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • 3. School of Life Science, Queensland University of Technology, Brisbane, Queensland, Australia.
  • 4. Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston Rd, Herston, Brisbane, Queensland, Australia.
  • 5. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • 6. Personalised Medicine, QIMR Berghofer Medical Research Institute, Herston Rd, Herston, Brisbane, Queensland, Australia; Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston Rd, Herston, Brisbane, Queensland, Australia. Electronic address: [email protected].
  • 7. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: [email protected].
PMID: 28545975 DOI: 10.1016/j.bmcl.2017.05.039
Abstract

RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast Cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 Inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for Cancer treatment.

Keywords
DNA repair; Homologous recombination; Inhibitor; RAD51; Triple-negative breast cancer.
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