Potent, non-thiol inhibitors of farnesyltransferase

• Published in: Bioorganic & medicinal chemistry letters Vol. 8; no. 23; pp. 3311 - 3316
• Main Authors: Breslin, Michael J., deSolms, S.Jane, Giuliani, Elizabeth A., Stokker, Gerald E., Graham, Samuel L., Pompliano, David L., Mosser, Scott D., Hamilton, Kelly A., Hutchinson, John H.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-12-1998; Elsevier
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Antineoplastic agents; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase; General aspects; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; Antineoplastic agent; Enzyme; Gene product; Transferases; Peptidomimetic compound; Enzyme inhibitor; Farnesyl-diphosphate farnesyltransferase; In vitro; Naphthalene derivatives; Organic sulfide; Pseudopeptide; Structure activity relation; Sulfur peptide; Onc gene; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00586-1

The structure-activity relationship of a series of non-thiol CaaX analogs, which are inhibitors of farnesyltransferase, is described. These inhibitors contain a substituted phenyl group at the N terminus, which may occupy a novel binding domain on the Ras protein.
The structure-activity relationships of a series of pseudotetrapeptides is described leading to the discovery of potent, non-thiol containing farnesyltransferase inhibitors. The most potent of these inhibitors contain a cyano or nitro substituted phenyl group at the N terminus connected by a thio-ether linkage.