B32B3

Virus protein R (Vpr) is a virion-associated protein expressed by lentiviruses, including HIV-1 and -2. It causes cell cycle arrest in infected cells by binding the mammalian Vpr-binding protein (VprBP) on the DDB1/CUL4 ubiquitin ligase complex. VprBP, also known as DDB1/CUL4-associated factor 1, acts as an adaptor protein but may also have other roles as part of the complex. B32B3 is a cell-permeable, ATP-competitive inhibitor of VprBP that blocks phosphorylation of histone 2A at Thr120 in DU-145 human prostate cancer cells (IC50 = 500 nM). It exhibits over 100-fold selectivity for VprBP against a panel of 33 other protein kinases. B32B3 strongly suppresses the proliferation of DU-145 cells, which overexpress VprBP, but not MCL normal human prostate cells, which have low levels of VprBP expression. At 5 mg/kg twice a week over three weeks, B32B3 inhibits the growth of DU-145 xenograft tumors in mice by 70-75%.