title: Imidazo[1,2-a]pyridine-based peptidomimetics as inhibitors of Akt.
abstract: We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide.
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Young B
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Chang Won
authors.initials: CW
authors.lastname: Kang
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Sujeewa
authors.initials: S
authors.lastname: Ranatunga
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Del Valle
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D057786:Peptidomimetics; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; C001439:imidazo(1,2-a)pyridine
keywords: Dipeptide surrogate; Kinase inhibitor; Peptide mimic; β-Strand mimic