Bmi1 is a central component of the Polycomb Repressive Complex 1 (PRC1) and is required for E3 ligase activity to ubiquitinate histone H2A. Multiple studies identified Bmi1 as oncogene promoting tumor growth in a variety of in vitro and in vivo animal models. Small molecule inhibitors of the Ring1B-Bmi1 E3 ligase activity have not been reported to date, but are highly desired as potential therapeutic agents targeting cancer stem cells.
Targeting the Ring E3 ligases with small molecules is a very challenging task due to the lack of well-defined substrate binding pockets and a complex biochemical assays required for enzymatic activity studies. We have identified compounds binding to Ring1B-Bmi1 based on NMR fragment screening. Further medicinal chemistry optimization resulted in potent inhibitors of E3 ligase activity. In cells, our compounds inhibit Ring1B-Bmi1 ubiquitin ligase activity at low micromolar concentrations. To our knowledge, these compounds represent the first small molecule inhibitors that directly bind to Ring1B-Bmi1 and inhibit its E3 ubiquitin ligase activity and have a strong potential for further development into anticancer agents.