Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents

J Med Chem. 2003 Jul 3;46(14):2973-84. doi: 10.1021/jm020587n.

S Jane deSolms ¹, Terrence M Ciccarone, Suzanne C MacTough, Anthony W Shaw, Carolyn A Buser, Michelle Ellis-Hutchings, Christine Fernandes, Kelly A Hamilton, Hans E Huber, Nancy E Kohl, Robert B Lobell, Ronald G Robinson, Nancy N Tsou, Eileen S Walsh, Samuel L Graham, Lorena S Beese, Jeffrey S Taylor

Affiliations

Affiliation

1 Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

PMID: 12825937 DOI: 10.1021/jm020587n

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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