Identification of highly potent inhibitors capable of blocking VprBP kinase activity and suppressing prostate tumor growth

Although VprBP can phosphorylate histone H2A and some non-histone proteins, it seems to selectively target specific substrates in a cancer type-dependent manner by an unknown mechanism. Here we report that VprBP is highly expressed in prostate cancer cells and inactivates a group of genes encoding critical regulators of cell growth and proliferation in a manner dependent on its kinase activity toward H2AT120.

As an extension of our previous finding of VprBP inhibitor B32B3, we also screened a series of small molecule compounds derived from B32B3 and identified B1486 as a second-generation VprBP inhibitor with much higher efficacy and potency. B1486 is far more effective in blocking VprBP-mediated H2AT120p and reactivating growth regulatory genes, resulting in a significantly lower proliferative capacity of prostate cancer cells.