title: From Type I to Type II: Design, Synthesis, and Characterization of Potent Pyrazin-2-ones as DFG-Out Inhibitors of PDGFRβ.
abstract: Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so-called DFG-in or DFG-out conformations, respectively. Based on our former study on highly selective platelet-derived growth factor receptor β (PDGFRβ) pyrazin-2-one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4-[(4-methylpiperazin-1-yl)methyl]-N-[3-[[6-oxo-5-(3,4,5-trimethoxyphenyl)-1H-pyrazin-3-yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity-based assays (300 kinases) and affinity-based assays (97 kinases) of these PDGFRβ type I (1; 5-(4-hydroxy-3-methoxy-phenyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazin-2-one) and II (5) inhibitors showing the same pyrazin-2-one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands.
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Bethke
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Pinchuk
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Renn
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Witt
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schlosser
authors.affiliation: Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Christian
authors.identifier: 0000-0003-1532-7826
authors.initials: C
authors.lastname: Peifer
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D015195:Drug Design; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: DFG-in/-out; PDGFRβ inhibition; kinase inhibitors; kinase selectivity; structure-based drug design