Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase.
A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (<or=80nM). An X-ray crystal structure of inhibitor 21 bound to rat farnesyltransferase is also presented.
Curtin
Michael L
ML
Department of Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. mike.curtin@abbott.com
Florjancic
Alan S
AS
Cohen
Jerome
J
Gu
Wen-Zhen
WZ
Frost
David J
DJ
Muchmore
Steven W
SW
Sham
Hing L
HL
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000187:drug effects; D006207:Half-Life; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D051379:Mice; D008958:Models, Molecular; D051381:Rats
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007202:Indicators and Reagents; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase