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.


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.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Protein Prenylation
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • rap1 GTP-Binding Proteins / metabolism
  • ras Proteins / metabolism


  • Antineoplastic Agents
  • Carrier Proteins
  • DNAJA1 protein, human
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • rap1 GTP-Binding Proteins
  • ras Proteins