Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold.
By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3'-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)methyl)amino-3'carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.
Ohkanda
Junko
J
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, USA.
Lockman
Jeffrey W
JW
Kothare
Mohit A
MA
Qian
Yimin
Y
Blaskovich
Michelle A
MA
Sebti
Said M
SM
Hamilton
Andrew D
AD
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011905:Genes, ras; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017368:Protein Prenylation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D009842:Oligopeptides; C411802:cysteinyl-valyl-isoleucyl-methionine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D020827:rap1 GTP-Binding Proteins; D015032:Zinc