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Protein–protein interactions as targets for small-molecule therapeutics in cancer

Published online by Cambridge University Press:  19 March 2008

Alex W. White ,
Andrew D. Westwell  and
Ghali Brahemi
Alex W. White*
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
Andrew D. Westwell
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
Ghali Brahemi
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
*
*Corresponding author: Alex W. White, Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK. Tel: +44 (0)29 2087 6308; Fax: +44 (0)29 2087 4149; E-mail: whiteaw@cf.ac.uk
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Abstract

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e8
Copyright
Copyright © Cambridge University Press 2008

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Further reading, resources and contacts

For general information on all aspects of cancer (science, treatment and research) visit:

http://www.cancerresearchuk.org/Google Scholar
http://www.cancerhelp.org.uk/Google Scholar
http://www.rcsb.org/pdbGoogle Scholar
http://en.wikibooks.org/wiki/Proteomics/Protein_-_Protein_InteractionsGoogle Scholar
http://www.geminx.com (Phase 2 clinical trial of GX015-070 small-molecule BCL 2 inhibitor)Google Scholar
http://www.roche.com/ (Developing the p53–MDM2 inhibitors; detailed presentation at http://www.roche.com/med_mb200605lv.pdf)Google Scholar