Quinazolinone derivatives as inhibitors of homologous recombinase RAD51.
Ward A, Dong L, Harris JM, Khanna KK, Al-Ejeh F, Fairlie DP, Wiegmans AP, Liu L.
Bioorg Med Chem Lett. 2017, In Press.
May 15. pii: S0960-894X(17)30520-6. doi: 10.1016/j.bmcl.2017.05.039.
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.
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