Overcoming P-Glycoprotein and ABCG2 as Obstacles to Therapeutic Delivery through Dimeric Substrate-Based Prodrugs
Abstract
The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are major obstacles to the effective delivery of therapeutic agents to various sites in the body. These transporters recognize hundreds of structurally and functionally unrelated compounds, many of which are therapeutics, and export these compounds outside of target cells or tissues. Herein, we describe the synthesis and characterization of bivalent molecules based on substrates of these transporters. Because P-gp and ABCG2 have multiple drug recognition sites, we hypothesize that bivalent molecules will occupy more than one drug binding site with a higher affinity, binding with a slower off-rate. Thus, these molecules should act as transport inhibitors. P-gp and ABCG2 expression at the blood-brain barrier (BBB) is a major impediment for drug delivery to the brain. The anti-psychotic agent paliperidone (Pal) is one such drug whose bioavailability is limited by these efflux transporters, ultimately reducing efficacy and requiring administration of a higher dose. We have developed a bivalent inhibitor based on the anti-psychotic agent Pal that is inhibits both P-gp and ABCG2 and reverts to monomeric Pal in a cellular model of the BBB. Expression of P-gp and ABCG2 maybe also an obstacle to cancer therapy contributing to the multidrug resistance (MDR) phenotype in a subset of patients with chronic myelogenous leukemia (CML). This inhibition of ABC transporters is an attractive strategy to improve penetration of therapeutic compounds. We applied the bivalent molecule approach to synthesize a library of anti-CML agents based on Dasatinib that inhibited P-gp and ABCG2 in a variety of cell lines, as well as in in vitro assays. Our lead compound also restored toxicity to MDR cell lines by inhibiting the action of P-gp.
Degree
Ph.D.
Advisors
Hrycyna, Purdue University.
Subject Area
Chemistry|Pharmaceutical sciences
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