Protein-protein interactions as targets for small-molecule therapeutics in cancer.
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.
White
Alex W
AW
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK. whiteaw@cf.ac.uk
Westwell
Andrew D
AD
Brahemi
Ghali
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013499:Surface Properties
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins