2-Arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase.
A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.
Trotter
B W
BW
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. bwesley_trotter@merck.com
Quigley
A G
AG
Lumma
W C
WC
Sisko
J T
JT
Walsh
E S
ES
Hamann
C S
CS
Robinson
R G
RG
Bhimnathwala
H
H
Kolodin
D G
DG
Zheng
W
W
Buser
C A
CA
Huber
H E
HE
Lobell
R B
RB
Kohl
N E
NE
Williams
T M
TM
Graham
S L
SL
Dinsmore
C J
CJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D017368:Protein Prenylation / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007210:Indoleacetic Acids; C015950:indoleacetamide; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins