title: Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.
abstract: Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in the identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4 nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.
authors.affiliation: Departments of Cancer Research, D-47B, Combinatorial Chemistry, D-4CP, and Anti-infective Research, D-47T, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. Henryk@lilly.com
authors.forename: K J
authors.initials: KJ
authors.lastname: Henry
authors.forename: J
authors.initials: J
authors.lastname: Wasicak
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: J
authors.initials: J
authors.lastname: Cohen
authors.forename: P
authors.initials: P
authors.lastname: Ewing
authors.forename: M
authors.initials: M
authors.lastname: Mitten
authors.forename: J J
authors.initials: JJ
authors.lastname: Larsen
authors.forename: D M
authors.initials: DM
authors.lastname: Kalvin
authors.forename: R
authors.initials: R
authors.lastname: Swenson
authors.forename: S C
authors.initials: SC
authors.lastname: Ng
authors.forename: B
authors.initials: B
authors.lastname: Saeed
authors.forename: S
authors.initials: S
authors.lastname: Cherian
authors.forename: H
authors.initials: H
authors.lastname: Sham
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C401326:N-(4-(1-cyclohexyl-3-ethylthioprop-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl)methionine; D010455:Peptides; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase