Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase

D J Augeri; S J O'Connor; D Janowick; B Szczepankiewicz; G Sullivan; J Larsen; D Kalvin; J Cohen; E Devine; H Zhang; S Cherian; B Saeed; S C Ng; S Rosenberg

doi:10.1021/jm980298s

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase

J Med Chem. 1998 Oct 22;41(22):4288-300. doi: 10.1021/jm980298s.

Authors

D J Augeri¹, S J O'Connor, D Janowick, B Szczepankiewicz, G Sullivan, J Larsen, D Kalvin, J Cohen, E Devine, H Zhang, S Cherian, B Saeed, S C Ng, S Rosenberg

Affiliation

¹ Departments of Cancer Research, D-47B, and Combinatorial Chemistry, D-4CP, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.

PMID: 9784104
DOI: 10.1021/jm980298s

Abstract

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.

MeSH terms

3T3 Cells
Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Cattle
Cell Line, Transformed
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Methionine / analogs & derivatives*
Methionine / chemical synthesis*
Methionine / chemistry
Methionine / pharmacology
Mice
Protein Prenylation / drug effects*
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Structure-Activity Relationship
ras Proteins / antagonists & inhibitors

Substances

Enzyme Inhibitors
Pyridines
Methionine
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I
p21(ras) farnesyl-protein transferase
ras Proteins