Structure-activity relationships of benzimidazole-based selective inhibitors of the mitogen activated kinase-5 signaling pathway.
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.
Flaherty
Patrick T
PT
Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, United States. flahertyp@duq.edu
Chopra
Ishveen
I
Jain
Prashi
P
Monlish
Darlene
D
Cavanaugh
Jane
J
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D048054:Mitogen-Activated Protein Kinase 7