Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/54748
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Type: Journal article
Title: How can we best use structural information on P-glycoprotein to design inhibitors?
Author: McDevitt, C.
Callaghan, R.
Citation: Pharmacology & Therapeutics, 2007; 113(2):429-441
Publisher: Pergamon-Elsevier Science Ltd
Issue Date: 2007
ISSN: 0163-7258
1879-016X
Statement of
Responsibility: 
Christopher A. McDevitt and Richard Callaghan
Abstract: This year marks the 30th anniversary of the discovery of the multidrug resistance (MDR) ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Since then a considerable research effort has attempted to provide a greater understanding of the biological enigma of “multidrug” efflux. Moreover, the growing correlation between P-gp expression and a negative prognosis or poor outcome for chemotherapy has sparked significant interest in the generation of inhibitors. How close are we to overcoming the unwanted actions of P-gp in resistant cancer following 30 years of research? The initial inhibitors were pre-existing clinically used compounds and exploited the broad specificity of P-gp. Unfortunately, the concentrations required to inhibit P-gp meant that these compounds generated considerable toxicity. Pharmacological investigations progressed to rational design using the 1st generation compounds as a template structure. Inherent toxicity of the drugs was reduced; however, pharmacokinetic interactions with the anticancer drugs were unsustainable. Generation of the most recent of inhibitors employed combinatorial chemistry to produce a handful of potent and selective P-gp inhibitors. Some of these drugs have progressed to clinical trials with poor results or in some cases, undisclosed progress. There remains a clear need for the generation of P-gp inhibitors and this review describes the potential for a structure-based design to facilitate this undertaking. In particular, the plethora of functional data can provide important regions on the protein that could conceivably be exploited as inhibitor targets.
Keywords: P-glycoprotein; Multidrug resistance; Cancer; Structure-based drug design; Membrane protein structure; ABC transporters
RMID: 0020093519
DOI: 10.1016/j.pharmthera.2006.10.003
Appears in Collections:Molecular and Biomedical Science publications

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