title: 4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKCζ.
abstract: Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) ζ via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKCζ, lacking inhibition of the most closely related isoform, PKCι, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKCζ without loss of potency compared to the cell-free assay.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fröhner
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lopez-Garcia
authors.forename: Sonja
authors.initials: S
authors.lastname: Neimanis
authors.forename: Nadja
authors.initials: N
authors.lastname: Weber
authors.forename: Jeanette
authors.initials: J
authors.lastname: Navratil
authors.forename: Frauke
authors.initials: F
authors.lastname: Maurer
authors.forename: Adriana
authors.initials: A
authors.lastname: Stroba
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000494:Allosteric Regulation; D001665:Binding Sites; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002474:Cell-Free System; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020298:U937 Cells; D000099221:Protein Kinase C zeta
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002087:Butyrates; D016328:NF-kappa B; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000099221:Protein Kinase C zeta; C061570:protein kinase N; C578562:PDPK1 protein, human