Terphenyl-Based Helical Mimetics That Disrupt the p53/HDM2 InteractionWe thank the National Institutes of Health for support of this work (GM35208 and GM69850). The HDM2 pQE40 construct was kindly provided by Dr. Christian Klein (Hoffmann-La Roche, Inc.).

The p53 protein plays a key role in the apoptosis pathway. Increased expression of wild-type p53 in stressed cells leads to cell-cycle arrest or apoptosis, whereas in normal cells p53 is present at very low levels owing to regulation by human double minute 2 (HDM2), which promotes the degradation of p53 through an ubiquitin-dependent proteasome pathway. The p53 protein is found in a mutated or inactive state in over 50% of cancerous tumors. Moreover, overexpression of HDM2 has been implicated in the development of cancerous tumors, such as human osteogenic sarcomas and soft-tissue sarcomas, as the overexpressed HDM2 abrogates the ability of p53 to induce cell-cycle arrest and apoptosis. For these reasons, disruption of the p53/HDM2 interaction by using small-molecule agents has become an important goal for anticancer-drug development. HDM2 regulates p53 by complex formation that involves amino acid residues 18–102 of HDM2 and a helical region of p53 (amino acids 16–28). Crystallographic analysis of the HDM2/p53 complex has revealed that three hydrophobic residues (F19, W23, L26) along one face of the p53 helical peptide are essential for binding (Figure 1a). Several groups