BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma

The Akt/PKB pathway plays a central role in tumor development and progression and is often up-regulated in different tumor types, including melanomas. We have recently reported on the in silico approach to identify putative inhibitors for Akt/PKB. Of the reported hits, we selected BI-69A11, a compound which was shown to inhibit Akt activity in in vitro kinase assays. Analysis of BI-69A11 was performed in melanoma cells, a tumor type that commonly exhibits up-regulation of Akt. Treatment of the UACC903 human melanoma cells, harboring the PTEN mutation, with BI-69A11 caused efficient inhibition of Akt S473 phosphorylation with concomitant inhibition of Akt phosphorylation of PRAS40. Treatment of melanoma cells with BI-69A11 also reduced Akt protein expression, which coincided with inhibition of Akt association with HSP-90. BI-69A11 treatment not only caused cell death of melanoma, but also prostate tumor cell lines. Notably, the effect of BI-69A11 on cell death was more pronounced in cells that express an active form of Akt. Significantly, intra-peritoneal injection of BI-69A11 caused effective regression of melanoma tumor xenografts, which coincided with elevated levels of cell death. These findings identify BI-69A11 as a potent inhibitor of Akt that is capable of eliciting effective regression of xenograft melanoma tumors.