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Exploitation of the ability of γ-tocopherol to facilitate membrane co-localization of Akt and PHLPP1 to develop PHLPP1-targeted Akt inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Mar 12; Vol. 58 (5), pp. 2290-8. Date of Electronic Publication: 2015 Feb 27. - Publication Year :
- 2015
-
Abstract
- Previously, we reported that Akt inactivation by γ-tocopherol (2) in PTEN-negative prostate cancer cells resulted from its unique ability to facilitate membrane co-localization of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase isoform 1), a Ser473-specific Akt phosphatase, through pleckstrin homology (PH) domain binding. This finding provided a basis for exploiting 2 to develop a novel class of PHLPP1-targeted Akt inhibitors. Here, we used 3 (γ-VE5), a side chain-truncated 2 derivative, as a scaffold for lead optimization. The proof-of-concept of this structural optimization was obtained by 20, which exhibited higher antitumor efficacy than 3 in PTEN-negative cancer cells through PHLPP1-facilitated Akt inactivation. Like 3, 20 preferentially recognized the PH domains of Akt and PHLPP1, as its binding affinities for other PH domains, including those of ILK and PDK1, were an order-of-magnitude lower. Moreover, 20 was orally active in suppressing xenograft tumor growth in nude mice, which underlines the translational potential of this new class of Akt inhibitor in PTEN-deficient cancers.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antioxidants chemistry
Antioxidants pharmacology
Cell Survival drug effects
Drug Design
Humans
Immunoblotting
Immunoprecipitation
Male
Mice
Mice, Nude
Phosphorylation drug effects
Protein Binding
Surface Plasmon Resonance
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Cell Membrane metabolism
Nuclear Proteins metabolism
Phosphoprotein Phosphatases metabolism
Prostatic Neoplasms drug therapy
Proto-Oncogene Proteins c-akt metabolism
gamma-Tocopherol chemistry
gamma-Tocopherol pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25689347
- Full Text :
- https://doi.org/10.1021/jm501751b