title: ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors.
abstract: 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.
authors: Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, People's Republic of China.|Department of Bio-Pharmacy/Mouse Cancer Clinic, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), Amsterdam, The Netherlands.
authors: Ping
authors: P
authors: Zhang
authors: Department of Bio-Pharmacy/Mouse Cancer Clinic, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), Amsterdam, The Netherlands.
authors: Mark C
authors: MC
authors: de Gooijer
authors: Department of Bio-Pharmacy/Mouse Cancer Clinic, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), Amsterdam, The Netherlands.
authors: Levi C M
authors: LC
authors: Buil
authors: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.|Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands.
authors: Jos H
authors: JH
authors: Beijnen
authors: Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
authors: Gang
authors: G
authors: Li
authors: Department of Bio-Pharmacy/Mouse Cancer Clinic, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), Amsterdam, The Netherlands.
authors: Olaf
authors: O
authors: van Tellingen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D001713:Biphenyl Compounds; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002460:Cell Line; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D001713:Biphenyl Compounds; C578195:EPZ005687; D004791:Enzyme Inhibitors; C577920:GSK-2816126; C586265:GSK343; D007191:Indazoles; D007211:Indoles; D009025:Morpholines; D011728:Pyridones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C000593333:tazemetostat
keywords: ABCB1; ABCG2; EZH2 inhibitor; brain penetration; pharmacokinetics