title: In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT.
abstract: The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation. Using proprietary docking software, 22 potential PH domain inhibitors were identified. Surface plasmon resonance spectroscopy was used to measure the binding of the compounds to the expressed PH domain of AKT followed by an in vitro activity screen in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. We identified a novel chemical scaffold in several of the compounds that binds selectively to the PH domain of AKT, inducing a decrease in AKT activation and causing apoptosis at low micromolar concentrations. Structural modifications of the scaffold led to compounds with enhanced inhibitory activity in cells. One compound, 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide, inhibited AKT and its downstream targets in cells as well as in pancreatic cancer cell xenografts in immunocompromised mice; it also exhibited good antitumor activity. In summary, a pharmacophore for PH domain inhibitors targeting AKT function was developed. Computer-aided modeling, synthesis, and testing produced novel AKT PH domain inhibitors that exhibit promising preclinical properties.
authors.affiliation: Department of Molecular and Cellular Biology, The University of Arizona, Tucson, Arizona 85721-0038, USA.
authors.forename: Sylvestor A
authors.initials: SA
authors.lastname: Moses
authors.forename: M Ahad
authors.initials: MA
authors.lastname: Ali
authors.forename: Song
authors.initials: S
authors.lastname: Zuohe
authors.forename: Lei
authors.initials: L
authors.lastname: Du-Cuny
authors.forename: Li Li
authors.initials: LL
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Lemos
authors.forename: Nathan
authors.initials: N
authors.lastname: Ihle
authors.forename: A Geoffrey
authors.initials: AG
authors.lastname: Skillman
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D005260:Female; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008958:Models, Molecular; D010750:Phosphoproteins / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
chemical_list: D001798:Blood Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C039077:platelet protein P47; D051057:Proto-Oncogene Proteins c-akt