Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/54748
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | How can we best use structural information on P-glycoprotein to design inhibitors? |
Author: | McDevitt, C. Callaghan, R. |
Citation: | Pharmacology and 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 |
DOI: | 10.1016/j.pharmthera.2006.10.003 |
Published version: | http://dx.doi.org/10.1016/j.pharmthera.2006.10.003 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.