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[1]. PTC-028 is an orally bioavailable inhibitor of stem cell factor BMI-1 in ovarian cancer. PTC-028 selectively inhibits cancer cells whereas normal cells remain unaffected. Depletion of BMI-1 by PTC-028 induces caspase-mediated apoptosis. PTC-028 (25-500 nM; 48 hours) significantly decreases CP20, OVCAR4 and OV90 epithelial ovarian cancer cells viability. PTC-028 (100 nM; 2-12 hours) increases the phosphorylated BMI-1 species in a time-dependent manner, and it subsequently reduces BMI-1 in the biochemical functional readout. PTC-028 (100 nM; 48 hours) decreases the expression of XIAP (X-linked inhibitor of apoptosis) and RIPK1 (Receptor-interacting protein kinase 1) while LC3B (microtubule-associated protein 1 light chain 3) levels remains unchanged compared to that of the control[1]. PTC-028 (15 mg/kg; administered orally twice weekly) causes ~94% (0.169 g) reduction in tumor weight compared to the control (average tumor weight, ~3g). PTC-028 (10 mg/kg or 20mg/kg; single oral doses) is administrated to the CD-1 mice. The Cmax is reached at both dose levels 1h post dose after which plasma concentrations slowly reduce[1].
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