title: Synthesis of GSK3β mimetic inhibitors of Akt featuring a novel extended dipeptide surrogate.
abstract: Akt is a cardinal nodal point in PI3K signaling pathway and confers resistance to apoptosis through inactivation of regulatory substrates such as GSK3β. Efforts to inhibit the kinase activity of Akt have largely focused on targeting the ATP-binding domain of Akt. Here, we present the design and synthesis of conformationally constrained GSK3β mimics featuring a novel extended dipeptide surrogate core. This effort resulted in the identification of a novel substrate mimetic Akt inhibitor (11) with low micromolar activity in vitro (Akt1 IC(50)=3.1 μM).
authors: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Sujeewa
authors: S
authors: Ranatunga
authors: Juan R
authors: JR
authors: Del Valle
mesh_terms: D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3