Targeting protein-protein interactions for cancer therapy.
An increasing number of protein-protein interactions have been identified as potential intervention points for the development of anticancer agents. However, such systems have historically been considered high-risk targets due to the relatively large interaction surfaces involved in protein-protein binding. This characterization has to be reexamined as progress has been made recently in identifying small-molecule inhibitors of several protein-protein systems in oncology including the p53-MDM2 interaction. This review presents a survey of protein-protein interactions that have been identified as potential oncology targets and evaluates their attractiveness in terms of drug discovery. The analysis focuses primarily on the structural characteristics of the participating binding sites, particularly the dimensions of the sites. Known ligands are also examined, especially with regard to their druglikeness.
Fry
David C
DC
Structural Chemistry Group, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. david.fry@roche.com
Vassilev
Lyubomir T
LT
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D008024:Ligands; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2