title: Design and synthesis of benzoazepin-2-one analogs as allosteric binders targeting the PIF pocket of PDK1.
abstract: A novel series of benzoazepin-2-ones were designed and synthesized targeting the PIF pocket of AGC protein kinases, among which a series of thioether-linked benzoazepin-2-ones were discovered to bind to the PIF pocket of 3-phosphoinositide-dependent kinase-1 (PDK1), and to displace the PIF peptide with an EC(50) values in the lower micromolar range. The structure-activity relationships (SARs) of the linker region, tail region, and distal region were explored to further optimize these novel binders which target the PIF pocket of PDK1. When tested in an in vitro PDK1 enzymatic assay using a peptide substrate, the benzodiazepin-2-ones increased the activity of the enzyme in a concentration-dependent fashion, indicating these compounds act as PDK1 allosteric activators. These new compounds may be further developed as therapeutic agents for the treatment of diseases where the PDK1-mediated AGC protein kinases are dysregulated.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Linyi
authors.initials: L
authors.lastname: Wei
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Gao
authors.forename: Robert
authors.initials: R
authors.lastname: Warne
authors.forename: Xueshi
authors.initials: X
authors.lastname: Hao
authors.forename: Dirksen
authors.initials: D
authors.lastname: Bussiere
authors.forename: Xiang-ju
authors.initials: XJ
authors.lastname: Gu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Uno
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases