| http://purl.uniprot.org/citations/25868794 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/25868794 | http://www.w3.org/2000/01/rdf-schema#comment | "Enhancer of Zeste Homolog 2 (EZH2) has emerged as a promising therapeutic target for treatment of a broad spectrum of tumors including gliomas. We explored the interactions of five novel, structurally similar EZH2 inhibitors (EPZ005687, EPZ-6438, UNC1999, GSK343 and GSK126) with P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). The compounds were screened by in vitro transwell assays and EPZ005687, EPZ-6438 and GSK126 were further tested in vivo using wild-type (WT), Abcb1 and/or Abcg2 knockout mice. All EZH2 inhibitors are transported by P-gp and BCRP, although in vitro the transporter affinity of GSK126 was obscured by very low membrane permeability. Both P-gp and Bcrp1 restrict the brain penetration of EPZ005687 and GSK126, whereas the brain accumulation of EPZ-6438 is limited by P-gp only and efflux of EPZ-6438 was completely abrogated by elacridar. Intriguingly, an unknown factor present in all knockout mouse strains causes EPZ005687 and EPZ-6438 retention in plasma relative to WT mice, a phenomenon not seen with GSK126. In WT mice, the GSK126 tissue-to-plasma ratio for all tissues is lower than for EPZ005687 or EPZ-6438. Moreover, the oral bioavailability of GSK126 is only 0.2% in WT mice, which increases to 14.4% in Abcb1;Abcg2 knockout mice. These results are likely due to poor membrane permeability and question the clinical usefulness of GSK126. Although all tested EZH2 inhibitors are substrates of P-gp and BCRP, restricting the brain penetration and potential utility for treatment of glioma, EPZ-6438 would be the most suitable candidate of this series."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.org/dc/terms/identifier | "doi:10.1002/ijc.29566"xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "Li G."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "Zhang P."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "Beijnen J.H."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "van Tellingen O."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "Buil L.C."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/author | "de Gooijer M.C."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/date | "2015"xsd:gYear |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/name | "Int J Cancer"xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/pages | "2007-2018"xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/title | "ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors."xsd:string |
| http://purl.uniprot.org/citations/25868794 | http://purl.uniprot.org/core/volume | "137"xsd:string |
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