title: Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2.
abstract: Palomid 529, a novel dual mTORC1/2 inhibitor has displayed interesting activities in experimental models and is a candidate for clinical evaluation. We have assessed the interaction of Palomid 529 with ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-gp/P-glycoprotein) and ABCG2 (BCRP/Breast Cancer Resistant Protein) by in vitro transwell assays, and their effects on the brain penetration using drug disposition analysis of i.v. and oral Palomid 529 in wild-type (WT) and Abcb1 and/or Abcg2 knockout (KO) mice. Palomid 529 lacked affinity for these transporters in vitro, in contrast to GDC-0941, a small molecule PI3K inhibitor, which we used as control substance for in vitro transport. The plasma AUCi.v. of micronized and DMSO formulated Palomid 529 was similar in WT and KO mice. Importantly, the brain and brain tumor concentration of Palomid 529 at a high dose (54 mg/kg) was also similar in both strains, whereas a less than 1.4-fold difference (p < 0.05) was found at the low (5.4 mg/kg) dose. Because of poor solubility, the oral bioavailability of micronized Palomid 529 was only 5%. Olive oil or spray-dried formulation greatly improved the bioavailability up to 50%. Finally, Palomid 529 effectively inhibits the orthotopic U87 glioblastoma growth. In summary, Palomid 529 is the first mTOR targeting drug lacking affinity for ABCB1/ABCG2 and having good brain penetration. This warrants further evaluation of Palomid 529 for treatment of high-grade gliomas and other intracranial malignancies.
authors: Department of Clinical Chemistry Preclinical Pharmacology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Hospital), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Fan
authors: F
authors: Lin
authors: Levi
authors: L
authors: Buil
authors: David
authors: D
authors: Sherris
authors: Jos H
authors: JH
authors: Beijnen
authors: Olaf
authors: O
authors: van Tellingen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D018374:LLC-PK1 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D001578:Benzopyrans; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C507084:Abcb1b protein, mouse; C533469:palomid 529
keywords: ABCB1; ABCG2; Palomid 529; blood-brain barrier; mTOR inhibitor