title: A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation.
abstract: The Akt pathway is frequently hyperactivated in human cancer and functions as a cardinal nodal point for transducing extracellular and intracellular oncogenic signals and, thus, presents an exciting target for molecular therapeutics. Here we report the identification of a small molecule Akt/protein kinase B inhibitor, API-1. Although API-1 is neither an ATP competitor nor substrate mimetic, it binds to pleckstrin homology domain of Akt and blocks Akt membrane translocation. Furthermore, API-1 treatment of cancer cells results in inhibition of the kinase activities and phosphorylation levels of the three members of the Akt family. In contrast, API-1 had no effects on the activities of the upstream Akt activators, phosphatidylinositol 3-kinase, phosphatidylinositol-dependent kinase-1, and mTORC2. Notably, the kinase activity and phosphorylation (e.g. Thr(P)(308) and Ser(P)(473)) levels of constitutively active Akt, including a naturally occurring mutant AKT1-E17K, were inhibited by API-1. API-1 is selective for Akt and does not inhibit the activation of protein kinase C, serum and glucocorticoid-inducible kinase, protein kinase A, STAT3, ERK1/2, or JNK. The inhibition of Akt by API-1 resulted in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor constitutively activated Akt. Furthermore, API-1 inhibited tumor growth in nude mice of human cancer cells in which Akt is elevated but not of those cancer cells in which it is not. These data indicate that API-1 directly inhibits Akt through binding to the Akt pleckstrin homology domain and blocking Akt membrane translocation and that API-1 has anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express hyperactivated Akt.
authors.affiliation: Departments of Molecular Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
authors.forename: Donghwa
authors.initials: D
authors.lastname: Kim
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Lili
authors.initials: L
authors.lastname: He
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Xia-Meng
authors.initials: XM
authors.lastname: Sun
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000970:Antineoplastic Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D009705:Nucleosides; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C548499:NSC 177223; C494087:Stat3 protein, mouse; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human