title: Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic.
abstract: Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-π stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland), Fax: (+41) 44-632-11-09.
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Lauber
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland), Fax: (+41) 44-632-11-09.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Hardegger
authors.affiliation: Department of Chemistry, University of Tromsø, Forskningsparken 3, Sykehusvegen 23, 9037 Tromsø (Norway).
authors.forename: Kazi A
authors.initials: KA
authors.lastname: Alam
authors.affiliation: Department of Chemistry, University of Tromsø, Forskningsparken 3, Sykehusvegen 23, 9037 Tromsø (Norway).
authors.forename: Bjarte A
authors.initials: BA
authors.lastname: Lund
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland), Fax: (+41) 44-632-11-09.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dumele
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland), Fax: (+41) 44-632-11-09.
authors.forename: Michael
authors.initials: M
authors.lastname: Harder
authors.affiliation: Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel (Switzerland).
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Department of Chemistry, University of Tromsø, Forskningsparken 3, Sykehusvegen 23, 9037 Tromsø (Norway). richard.engh@uit.no.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Engh
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland), Fax: (+41) 44-632-11-09. diederich@org.chem.ethz.ch.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005998:Glycine / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D006845:Hydrocarbons, Fluorinated; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; C015482:protein kinase modulator; D011494:Protein Kinases; D005998:Glycine
keywords: glycine-rich loop; interaction networks; kinases; molecular recognition; pyrrolidines; water replacement