title: 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.
authors.affiliation: Signal Transduction Program, Burnham Institute for Biomedical Research, 10901 N. Torrey Pines Rd. La Jolla, CA, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Gaitonde
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: Marianna
authors.initials: M
authors.lastname: Tcherpakov
authors.forename: Antimone
authors.initials: A
authors.lastname: Dewing
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Megan
authors.initials: M
authors.lastname: Riel-Mehan
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Gavin
authors.initials: G
authors.lastname: Robertson
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
chemical_list: C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018841:HSP90 Heat-Shock Proteins; D015363:Quinolones; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt