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. Crown Copyright (C) 2017 Published by Elsevier Ltd. All rights reserved.
|Authors||Ward, Ambber; Dong, Lilong; Harris, Jonathan M.; Khanna, Kum Kum; Al-Ejeh, Fares; Fairlie, David P.; Wiegmans, Adrian P.; Liu, Ligong|
|Journal||BIOORGANIC & MEDICINAL CHEMISTRY LETTERS|
|Funding Body||National Health and Medical Research Council of Australia (NHMRC)|