Design, synthesis and testing of novel anti-cancer agents targeting secretory pathway calcium ATPase

Abstract

Secretory pathway calcium ATPase (SPCA) 1 was found to be associated with basal-like breast cancers, which had the poorest prognosis with minimal therapeutic agents available. Increased expression of insulin-like growth factor receptor was identified in a study to possess a strong involvement in cancer initiation, proliferation and resistance to anti-cancer therapy. This finding had provided a window of opportunity to place SPCA1 as a new therapeutic target for basal-like breast cancer. The main aims were to fully understand the role of SPCA1 in basal-like breast cancer and to design, synthesise and test chemical compounds that would inhibit the growth of basal-like breast cancer cells in vitro. Additional focus was also placed on discovering sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) inhibitors to streamline the drug discovery process. The use of molecular modelling, virtual screening, chemical synthesis and biological assays had assisted with the decision of selecting potential compounds. At least three out of seven tested compounds had an effect on the intracellular calcium signals. However, the potency and selectivity of these compounds would need to be improved to become better SERCA inhibitors. Therefore more future work is warranted to further refine the potency and selectivity of these compounds on the target receptors.