| http://purl.uniprot.org/citations/25007344 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/25007344 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.org/dc/terms/identifier | "doi:10.1021/jm500373x"xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Johannes E."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Schmidt D."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Schlosser J."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Peifer C."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Totzke F."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Schachtele C."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Cappel D."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Horbert R."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/author | "Pinchuk B."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/date | "2015"xsd:gYear |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/name | "J Med Chem"xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/pages | "170-182"xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/title | "Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorbeta (PDGF-Rbeta) guided by water thermodynamics."xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://purl.uniprot.org/core/volume | "58"xsd:string |
| http://purl.uniprot.org/citations/25007344 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/25007344 |
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