Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and refractory to existing therapies. BMI-1 is part of the polycomb repressive complex 1 (PRC1). There is a statistically significant correlation between the high frequency of BMI-1-positive tumor cells and poor prognosis of patients according to the data analysis of multiple cancer types. And BMI-1 shows to be highly enriched in cancer stem cells (CSCs). It also acts as critical regulators of their self-renewal and differentiation. Interestingly, The targeting BMI-1 using gene therapy overcomes the chemo-resistance of tumor cells. BMI-1 knockdown prevents brain tumor formation in mice. The oncogene BMI-1 becomes an attractive therapeutic target. In this study, PTC-209 is a specific BMI-1 inhibitor with an IC₅₀ of 0.5 μM in HEK293T cell line. It also irreversibly impairs colorectal cancer-initiating cells (CICs).

PTC-209, a potent BMI-1 inhibitor, is a promising anticancer agent for the treatment of solid tumors.

PTC-209 efficiently downregulates BMI-1 expression and the histone H2AK119ub1 levels at microM concentrations.  Meanwhile, PTC-209 effectively inhibits glioblastoma cell proliferation and migration, and GSC self-renewal. Moreover, PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression. Strikingly, the glioblastoma growth is significantly attenuated by PTC-209 in a murine orthotopic xenograft model.

Moreover, PTC-209 causes a concentration- and time-dependent decrease in the cellular viability of lung cancer cells (LNM35 and A549), breast cancer cells (MDA-MB-231 and T47D), and colon cancer cells (HT-29, HCT8/S11, and HCT-116). Similarly, PTC-209 significantly decreases the growth of LNM35, A549, MDA-MB-231, and HT-29 clones and colonies in vitro and LNM35 and A549 tumor growth in the in vivo tumor xenograft model. In addition, PTC-209 at the non-toxic concentrations significantly reduced the migration of lung (LNM35 and A549) and breast (MDA-MB-231) cancer cells. PTC-209, at a concentration of 1 μM, enhances the anti-cancer effects of Frondoside-A in lung, breast, and colon cancer cells. It also enhances the effect of camptothecin in breast cancer cells and the effect of cisplatin in lung cancer cells in vitro. Furthermore, PTC-209 shows potent anti-myeloma activity and impairs the tumor microenvironment.