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

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.
AuthorsSupriya Gaitonde, Surya K De, Marianna Tcherpakov, Antimone Dewing, Hongbin Yuan, Megan Riel-Mehan, Stan Krajewski, Gavin Robertson, Maurizio Pellecchia, Ze'ev Ronai
JournalPigment cell & melanoma research (Pigment Cell Melanoma Res) Vol. 22 Issue 2 Pg. 187-95 (Apr 2009) ISSN: 1755-1471 [Print] England
PMID19175524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 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
Topics
  • Adenosine Triphosphate (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Benzimidazoles (pharmacology, therapeutic use)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Enzyme Activation (drug effects)
  • HSP90 Heat-Shock Proteins (metabolism)
  • Humans
  • Male
  • Melanoma (drug therapy, enzymology, pathology)
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Phosphorylation (drug effects)
  • Prostatic Neoplasms (pathology)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
  • Quinolones (pharmacology, therapeutic use)
  • Remission Induction
  • Xenograft Model Antitumor Assays

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