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

Pigment Cell Melanoma Res. 2009 Apr;22(2):187-95. doi: 10.1111/j.1755-148X.2009.00544.x. Epub 2009 Jan 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Male
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Quinolones / pharmacology*
  • Quinolones / therapeutic use
  • Remission Induction
  • Xenograft Model Antitumor Assays*

Substances

  • 3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one
  • Antineoplastic Agents
  • Benzimidazoles
  • HSP90 Heat-Shock Proteins
  • Quinolones
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt