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
  • 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.