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

Supriya Gaitonde, Surya K. De, Marianna Tcherpakov, Antimone Dewing, Hongbin Yuan, Megan Riel-Mehan, Stan Krajewski, Gavin Robertson, Maurizio Pellecchia, Ze'Ev Ronai

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalPigment Cell and Melanoma Research
Volume22
Issue number2
DOIs
StatePublished - Apr 2009

All Science Journal Classification (ASJC) codes

  • Oncology
  • General Biochemistry, Genetics and Molecular Biology
  • Dermatology

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