title: 3,5-Diphenylpent-2-enoic acids as allosteric activators of the protein kinase PDK1: structure-activity relationships and thermodynamic characterization of binding as paradigms for PIF-binding pocket-targeting compounds.
abstract: The modulation of protein kinase activities by low molecular weight compounds is a major goal of current pharmaceutical developments. In this line, important efforts are directed to the development of drugs targeting the conserved ATP binding site. However, there is very little experience on targeting allosteric, regulatory sites, different from the ATP binding site, in protein kinases. Here we describe the synthesis, cell-free activation potency, and calorimetric binding analysis of 3,5-diphenylpent-2-enoic acids and derivatives as allosteric modulators of the phosphoinositide-dependent kinase-1 (PDK1) catalytic activity. Our SAR results combined with thermodynamic binding analyses revealed both favorable binding enthalpy and entropy and confirmed the PIF-binding pocket of PDK1 as a druggable site. In conclusion, we defined the minimal structural requirements for compounds to bind to the PIF-binding pocket and to act as allosteric modulators and identified two new lead structures (12Z and 13Z) with predominating binding enthalpy.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Adriana
authors.initials: A
authors.lastname: Stroba
authors.forename: Francis
authors.initials: F
authors.lastname: Schaeffer
authors.forename: Valerie
authors.initials: V
authors.lastname: Hindie
authors.forename: Laura
authors.initials: L
authors.lastname: Lopez-Garcia
authors.forename: Iris
authors.initials: I
authors.lastname: Adrian
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fröhner
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D000495:Allosteric Site; D002151:Calorimetry; D019277:Entropy; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D005229:Fatty Acids, Monounsaturated; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases