Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Ambber Ward; Lilong Dong; Jonathan M Harris; Kum Kum Khanna; Fares Al-Ejeh; David P Fairlie; Adrian P Wiegmans; Ligong Liu

doi:10.1016/j.bmcl.2017.05.039

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. Epub 2017 May 15.

Authors

Ambber Ward¹, Lilong Dong², Jonathan M Harris³, Kum Kum Khanna⁴, Fares Al-Ejeh¹, David P Fairlie⁵, Adrian P Wiegmans⁶, Ligong Liu⁷

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: adrian.wiegmans@qimrberghofer.edu.au.
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: l.liu@imb.uq.edu.au.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cinnamates / chemical synthesis
Cinnamates / chemistry
Cinnamates / toxicity
DNA Damage / drug effects
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Female
Humans
Molecular Docking Simulation
Protein Structure, Tertiary
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / toxicity
Quinazolinones / chemistry*
Quinazolinones / pharmacology
Rad51 Recombinase / antagonists & inhibitors*
Rad51 Recombinase / metabolism
Structure-Activity Relationship
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology

Substances

Antineoplastic Agents
Cinnamates
Enzyme Inhibitors
Quinazolines
Quinazolinones
Rad51 Recombinase