MDM2 inhibitory peptides: Side chains cyclization as a method of stabilization of the biologically active helical conformation

MEDI 93

Krzysztof Krajewski, krajewsk@helix.nih.gov1, Zaneta Nikolovska-Coleska2, Shaomeng Wang, shaomeng@umich.edu2, and Peter P. Roller1. (1) Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Boyles Street, Bldg 376, Frederick, MD 21702-1201, (2) Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109
The p53 tumor suppressor protein regulates cell proliferation by induction of growth arrest or apoptosis in response to DNA damage. In many cancer cells p53 is deactivated by binding to the MDM2 oncoprotein. The disruption of the p53/MDM2 protein-protein interaction is therefore an attractive approach for cancer therapy. The X-ray structures of the amino-terminal domain of MDM2 bound to inhibitory peptides (p53 sequence fragment and an analog, PDB#: 1YCR and 1T4F) revealed that MDM2 has a deep hydrophobic cleft on which the inhibitory peptides binds as amphipathic α-helixes. We designed several analogs of p53 sequence in which the side chains of amino acids in positions i and i+4 or i and i+3 are covalently linked (cyclizations or bicyclizations via amide or thioether bonds formation) to stabilize the active helical conformations. We will present the synthesis, conformational studies, and inhibitory activity assay results for these peptides. We observed (CD spectroscopy) a stabilization of the ordered conformations after cyclization of the peptides. The most potent cyclic peptides have the Ki values below 10nM.
 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006