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 journalArticle

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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 1 2009

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Heterografts
Melanoma
Tumors
Cell death
Phosphorylation
Cell Death
Neoplasms
3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one
Tumor Cell Line
Computer Simulation
Prostate
Assays
Phosphotransferases
Up-Regulation
Therapeutics
Cells
Association reactions
Mutation
Injections
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

Cite this

Gaitonde, S., De, S. K., Tcherpakov, M., Dewing, A., Yuan, H., Riel-Mehan, M., ... Ronai, ZE. (2009). BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. Pigment Cell and Melanoma Research, 22(2), 187-195. https://doi.org/10.1111/j.1755-148X.2009.00544.x
Gaitonde, Supriya ; De, Surya K. ; Tcherpakov, Marianna ; Dewing, Antimone ; Yuan, Hongbin ; Riel-Mehan, Megan ; Krajewski, Stan ; Robertson, Gavin ; Pellecchia, Maurizio ; Ronai, Ze'Ev. / BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. In: Pigment Cell and Melanoma Research. 2009 ; Vol. 22, No. 2. pp. 187-195.
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Gaitonde, S, De, SK, Tcherpakov, M, Dewing, A, Yuan, H, Riel-Mehan, M, Krajewski, S, Robertson, G, Pellecchia, M & Ronai, ZE 2009, 'BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma', Pigment Cell and Melanoma Research, vol. 22, no. 2, pp. 187-195. https://doi.org/10.1111/j.1755-148X.2009.00544.x

BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. / Gaitonde, Supriya; De, Surya K.; Tcherpakov, Marianna; Dewing, Antimone; Yuan, Hongbin; Riel-Mehan, Megan; Krajewski, Stan; Robertson, Gavin; Pellecchia, Maurizio; Ronai, Ze'Ev.

In: Pigment Cell and Melanoma Research, Vol. 22, No. 2, 01.04.2009, p. 187-195.

Research output: Contribution to journalArticle

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T1 - BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma

AU - Gaitonde, Supriya

AU - De, Surya K.

AU - Tcherpakov, Marianna

AU - Dewing, Antimone

AU - Yuan, Hongbin

AU - Riel-Mehan, Megan

AU - Krajewski, Stan

AU - Robertson, Gavin

AU - Pellecchia, Maurizio

AU - Ronai, Ze'Ev

PY - 2009/4/1

Y1 - 2009/4/1

N2 - 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.

AB - 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.

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