Dual Protein Farnesyltransferase−Geranylgeranyltransferase-I Inhibitors as Potential Cancer Chemotherapeutic Agents
Journal of Medicinal Chemistry2003Vol. 46(14), pp. 2973–2984
Citations Over TimeTop 11% of 2003 papers
S. J. DESOLMS, Terrence M. Ciccarone, Suzanne C. MacTough, Anthony W. Shaw, Carolyn A. Buser, Michelle Ellis-Hutchings, Christine Fernandes, Kelly Hamilton, Hans E. Huber, Nancy E. Kohl, Robert B. Lobell, R. Robinson, Nancy N. Tsou, Eileen S. Walsh, Samuel Graham, L.S. Beese, Jeffrey S. Taylor
Abstract
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
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