title: Submonomer synthesis of azapeptide ligands of the Insulin Receptor Tyrosine Kinase domain.
abstract: Azapeptide ligands of the Insulin Receptor Tyrosine Kinase (IRTK) were developed by solid-phase submonomer azapeptide synthesis in sufficient isolated yields (36-55%) and purities >95% for structure-activity relationship studies. The azapeptides adopted folded geometries with some proportion of random coil according to CD and NMR spectroscopy. In vitro phosphorylation of the IRTK domain in the presence of azapeptides produced a lead inhibitor, Ac-DIazaYET-NH2 (∼50% at 400 μM) whereas the [aza-DOPA(3)] and [aza-Glu(4)] analogs were found to stimulate IRTK phosphorylations. Thus, azapeptide ligands of the IRTK provide important modulatory activity of this important class of enzymes for anti-cancer and related applications in drug discovery.
authors.affiliation: Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Ave., South Orange, NJ 07079, USA.
authors.forename: Lathamol A
authors.initials: LA
authors.lastname: Kurian
authors.affiliation: Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Ave., South Orange, NJ 07079, USA.
authors.forename: Tammy A
authors.initials: TA
authors.lastname: Silva
authors.affiliation: Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Ave., South Orange, NJ 07079, USA. Electronic address: david.sabatino@shu.edu.
authors.forename: David
authors.initials: D
authors.lastname: Sabatino
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D008024:Ligands; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C410467:insulin receptor tyrosine kinase; D011505:Protein-Tyrosine Kinases
keywords: Azapeptide; IRTK inhibition; Insulin Receptor Tyrosine Kinase; Peptidomimetics