Targeting protein-protein interactions: lessons from p53/MDM2.
The tremendous challenge of inhibiting therapeutically important protein-protein interactions has created the opportunity to extend traditional medicinal chemistry to a new class of targets and to explore nontraditional strategies. Here we review a widely studied system, the interaction between tumor suppressor p53 and its natural antagonist MDM2, for which both traditional and nontraditional approaches have been reported. This system has been a testing ground for novel proteomimetic scaffold-based strategies, i.e., for attempts to mimic the recognition surface displayed by a folded protein with unnatural oligomers. Retroinverso peptides, peptoids, terphenyls, beta-hairpins, p-oligobenzamides, beta-peptides, and miniproteins have all been explored as inhibitors of the p53/MDM2 interaction, and we focus on these oligomer-based efforts. Traditional approaches have been successful as well, and we briefly review small molecule inhibitors along with other strategies for reactivation of the p53 pathway, for comparison with oligomer- based approaches. We close with comments on an emerging dichotomy among protein-protein interaction targets.
Murray
Justin K
JK
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA.
Gellman
Samuel H
SH
D000818:Animals; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2