Evaluating the mechanism and therapeutic potential of PTC-028, a novel inhibitor of BMI-1 function in ovarian cancer

BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathological significance of BMI-1, small molecule inhibitors against BMI1 are recently being developed. In the current study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by post-translational modification We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays whereas normal cells remain unaffected. Mechanistically, hyper-phosphorylation mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC-028, as a single agent exhibits significant antitumor activity comparable to the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited.

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