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Ref Type Journal Article
PMID (19175524)
Authors Gaitonde S, De SK, Tcherpakov M, Dewing A, Yuan H, Riel-Mehan M, Krajewski S, Robertson G, Pellecchia M, Ronai Z
Title BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma.
Journal Pigment cell & melanoma research
Vol 22
Issue 2
Date 2009 Apr
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BI-69A11 BI-69A11 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BI-69A11 BI 69A11 Akt1 Inhibitor 6 BI-69A11 binds to and inhibits the activity of Akt1 in the ATP binding pocket leading to inhibition of Akt signaling in cancer cells (PMID: 19175524, PMID: 26631035, PMID: 30904616).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN mutant melanoma sensitive BI-69A11 Preclinical - Cell line xenograft Actionable In a preclinical study, BI-69A11 resulted in antitumor activity in a melanoma cell line harboring a PTEN mutation, including induction of cell death in culture, and in xenograft models, tumor growth inhibition and tumor regression (PMID: 19175524). 19175524