An Ultrahigh Affinity d-Peptide Antagonist Of MDM2

• Published in: Journal of medicinal chemistry Vol. 55; no. 13; pp. 6237 - 6241
• Main Authors: Zhan, Changyou, Zhao, Le, Wei, Xiaoli, Wu, Xueji, Chen, Xishan, Yuan, Weirong, Lu, Wei-Yue, Pazgier, Marzena, Lu, Wuyuan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.07.2012
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Crystallography, X-Ray; Drug Design; Humans; Inhibitory Concentration 50; Models, Molecular; Oligopeptides - chemistry; Oligopeptides - pharmacology; Proteolysis; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Structure-Activity Relationship; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3005465

The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal d-peptide antagonists of MDM2, termed DPMI-α, β, γ. The prototypic d-peptide inhibitor DPMI-α binds (25–109)MDM2 at an affinity of 220 nM and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a superactive d-peptide antagonist of MDM2, termed DPMI-δ, of which the binding affinity for (25–109)MDM2 has been improved over DPMI-α by 3 orders of magnitude (K d = 220 pM). X-ray crystallographic studies validate DPMI-δ as an exceedingly potent inhibitor of the p53–MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.