title: Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents.
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.
authors.affiliation: Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: S Jane
authors.initials: SJ
authors.lastname: deSolms
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Ciccarone
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: MacTough
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Shaw
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Michelle
authors.initials: M
authors.lastname: Ellis-Hutchings
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hamilton
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Lorena S
authors.initials: LS
authors.lastname: Beese
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Taylor
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins