Editors' ChoiceProtein Interactions

Cancer Drug in the Pocket

Science's STKE  10 Feb 2004:
Vol. 2004, Issue 219, pp. tw47
DOI: 10.1126/stke.2192004TW47

The p53 pathway plays a pivotal role in the prevention of tumor development and has elicited considerable interest as a potential target for cancer drug discovery. In a systematic screen of synthetic chemicals, Vassilev et al. identified a series of small molecules (cis-imidazoline analogs, called "nutlins") that inhibit the interaction of p53 with MDM2, a protein that antagonizes p53's tumor suppressor function. The nutlins act by binding MDM2 within its p53-binding pocket, resulting in p53 activation in tumor cells with subsequent cell-cycle arrest and apoptosis. When orally administered to mice, the nutlins significantly inhibited tumor growth. These results validate the concept that small molecules targeting protein-protein interactions can be developed into effective therapeutics.

L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs, C. Klein, N. Fotouhi, E. A. Liu, In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848 (2004). [Abstract] [Full Text]