Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents.
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.
deSolms
S Jane
SJ
Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Ciccarone
Terrence M
TM
MacTough
Suzanne C
SC
Shaw
Anthony W
AW
Buser
Carolyn A
CA
Ellis-Hutchings
Michelle
M
Fernandes
Christine
C
Hamilton
Kelly A
KA
Huber
Hans E
HE
Kohl
Nancy E
NE
Lobell
Robert B
RB
Robinson
Ronald G
RG
Tsou
Nancy N
NN
Walsh
Eileen S
ES
Graham
Samuel L
SL
Beese
Lorena S
LS
Taylor
Jeffrey S
JS
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
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