Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.
Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.
Departments of Cancer Research, D-47B, and Combinatorial Chemistry, D-4CP, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
D J
DJ
Augeri
S J
SJ
O'Connor
D
D
Janowick
B
B
Szczepankiewicz
G
G
Sullivan
J
J
Larsen
D
D
Kalvin
J
J
Cohen
E
E
Devine
H
H
Zhang
S
S
Cherian
B
B
Saeed
S C
SC
Ng
S
S
Rosenberg
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D017368:Protein Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D011725:Pyridines; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins