Using Computer-Aided Drug Design and Optimization of Lead Compound to Develop Drug Candidate for Treatment of Breast Cancer

Triple negative breast cancers (TNBCs) are characterized by absence of estrogen and progesterone receptor expression, and by a lack of overexpression of human epidermal growth factor receptor 2 (HER2). It accounts for some 15-20% of all breast cancers. It is generally associated with high tumor grade, basal cytokeratins 5/6, p53 overexpression, and BRCA1 mutations. Compared to other types of breast cancer, TNBCs are often the most aggressive and have fewer treatment options. Human topoisomerase II binding protein 1 (TopBP1) has been identified as a protein interacting with topoisomerase II in a yeast two-hybrid screen. TopBP1 contains nine BRCA1 carboxyl-terminal (BRCT) domains with separate functions in DNA replication, DNA damage repair, apoptosis, and cell cycle checkpoints signaling. In cancer, TopBP1 is upregulated through deregulation of the pRb pathway or other mechanisms. Overexpression of TopBP1 in some cancer cells (e.g. TNBCs and ovary cancer) then may inhibit both p53 and E2F1 activities in checkpoint or apoptosis. In this manner, upregulation of TopBP1 links pRb and p53 pathways in cancer. In addition, BRCT7/8 domains of ToPBP1 are responsible for TopBP1 oligomerization and p53 binding, inhibitors that bind the domains may reactivate E2F1 and p53 apoptotic activities and inhibit mutp53 GOF (gain of function). BRCT7/8 domains are also required for DNA repair. Thus, the inhibition of TopBP1-BRCT7/8 will be a new target for the treatment of triple negative breast cancers. By computer-aided drug design (CADD), molecular docking and in vitro bioactivity test, one compound with chromone-2-one skeleton possessing the inhibition of TopBP1-BRCT7/8 is found. Currently, there is no report related to chromone analogues to inhibit TopBP1-BRCT7/8. In seeking new lead candidate on the inhibiting TopBP1-BRCT7/8, this lead compound will be optimized. The synthesized analogues will be coupled with molecular docking and evaluated their bioactivities in cancer cells to obtain lead candidate. The results will provide drug candidate for the treatment of TNBCs.