PTC-028 is an Inhibitor of BMI-1 with Activity in Ovarian Cancer
Posted On 2019-07-05
Epithelial ovarian cancers are the most common type of ovarian cancer. BMI-1 over-expresses in epithelial ovarian cancer. Targeting BMI-1 sensitizes a variety of cancer cells to chemo-therapeutics. The B cell-specific moloney murine leukemia virus integration site 1 (Bmi-1) is a transcriptional receptor of the polycomb gene family. BMI-1 involves in several cellular processes including cell-cycle regulation, apoptosis, and maintenance of adult and neoplastic stem cells. Further, Bmi-1 expression associates with malignant transformation, tumor progression, metastatic disease, and poor prognosis in human malignancies.
Nowadays, researchers aim to evaluate the sensitivity of Bmi-1 expression as a diagnostic marker for malignant change in a case series of carcinoma ex pleomorphic adenoma (CXPA) at an early phase of carcinomatous progression. BMI-1, a stem cell factor, frequently up-regulates in several malignancies. BMI-1 proto-oncogene is a member of the polycomb repressor complex 1 (PRC1). Especially, BMI-1 mediates gene silencing by regulating chromatin structure.
PTC-028 is an orally bio-available compound that decreases BMI-1 levels by post-translational modification. In vitro, PTC-028 selectively inhibits ovarian cancer cells in clonal growth and viability assays whereas normal cells remain unaffected. Moreover, PTC-028 also induces caspase-dependent apoptosis in ovarian cancer cells. In vivo, orally administered PTC-028, as a single agent exhibits significant anti-tumor activity compared to the standard Cisplatin/Paclitaxel therapy in an orthotopic mouse model of ovarian cancer.
In summary, PTC-028 induces hyper-phosphorylation and gradual depletion of BMI-1. This effect results in depletion of ATP and induction of mitochondrial ROS with decreased expression of both RIPK1 and XIAP. As a result, leading to activation of the caspase cascade. Therefore, PTC-028 could potentially be used as an effective therapeutic for epithelial ovarian cancer.
Dey A, et al. Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer. Mol Cancer Ther. 2018 Jan;17(1):39-49.