Structure–activity relationships of benzimidazole-based selective inhibitors of the mitogen activated kinase-5 signaling pathway

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 22; pp. 8054 - 8060
• Main Authors: Flaherty, Patrick T., Chopra, Ishveen, Jain, Prashi, Monlish, Darlene, Cavanaugh, Jane
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2010; Elsevier
• Subjects: Antineoplastic agents; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Epidermal Growth Factor - metabolism; ERK; ERK5; General aspects; HEK293 Cells; Hoechst 33258; Humans; Medical sciences; MEK; MEK5; Mitogen-Activated Protein Kinase 7 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 7 - metabolism; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Signal Transduction; Structure-Activity Relationship; MEK; Hoechst 33258; MEK5; Benzimidazole; ERK5; ERK; Antineoplastic agent; Ether; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; Mitogen-activated protein kinase; Selectivity; In vitro; Signal transduction; Structure activity relation; Benzimidazole derivatives; Bicyclic compound; Aromatic compound; Mitogen-activated protein kinase kinase; Aromatic amine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.017

Inhibition of EGF-mediated ERK5 phosphorylation is examined for several 1-isopropyl-4-amino-6-ether linked benzimidazole-based compounds. In a prior communication we identified a novel class of benzimidazole-based inhibitors of EGF-induced phosphorylation of ERK5. In this paper we examine the biological activity of several 1-isopropyl-4-amino-6-ether linked benzimidazole-based compounds for their ability to selectively inhibit EGF-mediated ERK5 phosphorylation; potential utility of variation at the 6-position was indicated by the initial structural feature survey. Modification of EGF-induced formation of pERK1/2 and pERK5 in HEK293 cells were analyzed by Western blot analysis. Subsequent analysis of selected compounds in a high-throughput multiple kinase scan and the NCI 60-cell-line screen is presented.