title: Exploitation of the ability of γ-tocopherol to facilitate membrane co-localization of Akt and PHLPP1 to develop PHLPP1-targeted Akt inhibitors.
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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Ribai
authors.initials: R
authors.lastname: Yan
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Chuang
authors.forename: Naval
authors.initials: N
authors.lastname: Kapuriya
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chou
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Lai
authors.forename: Hsin-Wen
authors.initials: HW
authors.lastname: Chang
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D024504:gamma-Tocopherol / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D009687:Nuclear Proteins; D024504:gamma-Tocopherol; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases