Ward Ambber, Dong Lilong, Harris Jonathan M, Khanna Kum Kum, Al-Ejeh Fares, Fairlie David P, Wiegmans Adrian P, Liu Ligong
Personalised Medicine, QIMR Berghofer Medical Research Institute, Herston Rd, Herston, Brisbane, Queensland, Australia.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Bioorg Med Chem Lett. 2017 Jul 15;27(14):3096-3100. doi: 10.1016/j.bmcl.2017.05.039. Epub 2017 May 15.
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.
RAD51是同源重组DNA修复途径的重要组成部分，在包括侵袭性三阴性乳腺癌（TNBC）在内的耐药癌症中过表达。一种旨在改善患者治疗效果的策略是通过小分子抑制RAD51，从而使肿瘤细胞对DNA损伤性辐射和/或化疗敏感。在此，我们报告了喹唑啉酮衍生物文库的构效关系。与化合物B02相比，一种新型RAD51抑制剂（17）在一组TNBC细胞系中对细胞生长的抑制作用增强了15倍，对辐射诱导的RAD51病灶形成的抑制作用增加了约2倍。此外，化合物17显著抑制TNBC细胞对DNA损伤的敏感性，这意味着它可能是一种针对癌症治疗的靶向疗法。
