title: Hydroxamic acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase.
abstract: The rational design, synthesis, and activity of novel, hydroxamic acid-based, collective bisubstrate analog inhibitors of farnesyl protein transferase (FPT) is described. This class of compounds differ structurally from the conventional FPT inhibitors by being non-sulfhydryl and by being bisubstrate based rather than peptide or FPP derived inhibitors. Whereas replacement of the sulfhydryl group of tetrapeptide CVLS (I50 = 1 microM) by an N-methylhydroxamic acid had a deleterious effect (10, I50 > 360 microM), moderate inhibition was realized with 16 (I50 = 42.5 microM), a bisubstrate analog involving anchorage of farnesyl and tripeptide groups by a hydroxamic acid-embedded linker. Starting from 16, a 1 order of magnitude improvement in in vitro potency was obtained by optimization of the linker (20, I50 = 4.35 microM). An additional 13-fold enhancement was achieved by substituting the tripeptide moiety VLS in 20 by VVM (23, I50 = 0.33 microM). The dependence of these inhibitors on their peptide and farnesyl subunits is suggestive of their bisubstrate nature. Compound 23 (I50 = 0.33 microM) is 2 orders of magnitude better in activity compared to the initial lead 16 [I50 = 42.5 microM) and is effective in blocking prenylation of protein in whole cells including p21ras.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: D V
authors.initials: DV
authors.lastname: Patel
authors.forename: M G
authors.initials: MG
authors.lastname: Young
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.forename: L
authors.initials: L
authors.lastname: Hunihan
authors.forename: B J
authors.initials: BJ
authors.lastname: Dean
authors.forename: E M
authors.initials: EM
authors.lastname: Gordon
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D001345:Autoradiography; D004247:DNA / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011905:Genes, ras; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008970:Molecular Weight; D013329:Structure-Activity Relationship; D014162:Transfection; D014166:Transferases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D004247:DNA; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase