2-Arylindole-3-acetamides: FPP-Competitive inhibitors of farnesyl protein transferase

• Published in: Bioorganic & medicinal chemistry letters 2001-04, Vol.11 (7), p.865-869
• Main Authors: Trotter, B.Wesley, Quigley, Amy G., Lumma, William C., Sisko, John T., Walsh, Eileen S., Hamann, Christian S., Robinson, Ronald G., Bhimnathwala, Hema, Kolodin, D.Garrett, Zheng, Wei, Buser, Carolyn A., Huber, Hans E., Lobell, Robert B., Kohl, Nancy E., Williams, Theresa M., Graham, Samuel L., Dinsmore, Christopher J.
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Antineoplastic agents; Biological and medical sciences; Carrier Proteins - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; General aspects; Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins; Humans; Indoleacetic Acids - chemical synthesis; Indoleacetic Acids - metabolism; Indoleacetic Acids - pharmacology; Medical sciences; Pharmacology. Drug treatments; Protein Prenylation - drug effects; Protein Prenylation - physiology; ras Proteins - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00061-0

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed. Graphic