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.