The synthesis and biological evaluation of a series of potent dual inhibitors of farnesyl and geranyl-Geranyl protein transferases.
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. tom_tucker@merck.com
Thomas J
TJ
Tucker
Marc T
MT
Abrams
Carolyn A
CA
Buser
Joseph P
JP
Davide
Michelle
M
Ellis-Hutchings
Christine
C
Fernandes
Jackson B
JB
Gibbs
Samuel L
SL
Graham
George D
GD
Hartman
Hans E
HE
Huber
Dongming
D
Liu
Robert B
RB
Lobell
William C
WC
Lumma
Ronald G
RG
Robinson
John T
JT
Sisko
Anthony M
AM
Smith
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D020668:rap GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D020668:rap GTP-Binding Proteins