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 AUC i.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.

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

“…Moreover, we did not evaluated sufficient doses of INK128 to determine the therapeutic window, a critical parameter to determine its potential clinical utility of TOR-KIs against HIV. Future studies should determine the therapeutic window and dosing schedules for INK128 and additional TOR-KIs (18,(49)(50)(51)(52)(53)(54) so as to identify the most effective and safest approach to inhibit HIV.…”

P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib

“…Concentration Equilibrium Transwell Assays (CETAs) were performed as described previously [15]. In short, MDCK or LLC cells were seeded onto Transwell microporous polycarbonate membrane filters (3.0 μm pore size, 24 mm diameter; Costar Corning, Corning, NY, USA) at a density of 2×10 6 cells per well in complete MEM medium and allowed to grow into a monolayer.…”

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

“…To determine whether rapamycin, AZD8055, NVP-BEZ235, and ZSTK474 are substrates of murine Abcb1a (Mdr1a), human ABCB1 (MDR1), murine Abcg2, and/or human ABCG2, we analyzed the translocation of these compounds in concentration equilibrium transport assays (CETA) as described previously (22). To this end, we used the parental LLC pig-kidney cell line (LLC-PK1) and sublines transduced with murine Abcb1a (LLC-Mdr1a) or human ABCB1 (LLC-MDR1) and the parental Madine Darby Canine Kidney (MDCK) type II cell line (MDCKII-parental) and murine Abcg2 (MDCKII-Bcrp1) or human ABCG2-transduced sublines (MDCKII-BCRP).…”