title: Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics.
abstract: In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC50 = 0.5 μM). Furthermore, 2 was shown to be selective for PDGF-Rβ in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rβ homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 μM in a PDGF-Rβ enzymatic assay also showing activity against PDGF-R dependent cancer cells.
authors.affiliation: Institute of Pharmacy, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, D-24116 Kiel, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Horbert
authors.forename: Boris
authors.initials: B
authors.lastname: Pinchuk
authors.forename: Eugen
authors.initials: E
authors.lastname: Johannes
authors.forename: Joachim
authors.initials: J
authors.lastname: Schlosser
authors.forename: Dorian
authors.initials: D
authors.lastname: Schmidt
authors.forename: Daniel
authors.initials: D
authors.lastname: Cappel
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Christian
authors.initials: C
authors.lastname: Peifer
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D054852:Small Molecule Libraries; D014867:Water; D000255:Adenosine Triphosphate; D020797:Receptor, Platelet-Derived Growth Factor beta