Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway Patrick T. Flaherty a, * , Ishveen Chopra a , Prashi Jain a , Shuyan Yi a , Erika Allen b , Jane Cavanaugh b a Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, USA b Division of Pharmacology, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA 15282, USA article info Article history: Received 5 February 2010 Revised 2 March 2010 Accepted 5 March 2010 Available online 10 March 2010 Keywords: MEK5 ERK5 Inhibitor Benzimidazole abstract The MEK-signaling pathways are complex but critical signaling cascades that correlate an extracellular signaling event with internal cell processes. To date at least seven MEK isozymes have been identified. MEK5, in particular, is upregulated in multiple forms of tumors. Analysis of the EGF-induced MEK5 sig- naling cascade in cultured HEK cells has identified compounds that can inhibit MEK5 phosphorylation of ERK5; observed biological activity is dependent on chemical variation. Ó 2010 Elsevier Ltd. All rights reserved. The mitogen activated protein kinase (MAPK) pathways are a family of related, and often interconnected, signaling pathways that relay input from extracellular origins and interpret the resul- tant outcome in the context of the current biological milieu. 1–8 There have been multiple reviews 1,3,9 and several critical advances regarding the categorization, 10,11 the intrinsic biochemistry, 12,13 and the relevance to human disease states 9,14,15 displayed by var- ious members of the MAPK family. The sequence of signaling typically originates with ligand bind- ing or extracellular stressor followed by one of three transduction mechanisms; 3,16 receptor tyrosine kinase activation, G-protein coupled receptor activation, or hormone receptor transduction. The MAPK pathways exist as a series of phosphorylation events where one kinase (mitogen-activated kinase kinase kinase: MEKK) phosphorylates a second kinase (mitogen-activated kinase kinase: MEK), which then phosphorylates a third kinase (extracellular sig- nal-regulated kinase: ERK). This third kinase, or ERK, is typically translocated to effect modification of cellular function in a specific subcellular compartment. 17 Multiple phosphorylation states of ERKs have been demonstrated and may direct subcellular traffick- ing and substrate preference for phospho-ERK 15,17 (Fig. 1). MEKs uniquely display a high degree of substrate specificity. This selectively is derived from multiple interactions of a MEK’s D domain with a unique complementary CD domain on the sub- strate ERK, association with scaffolding proteins, 13,18 association 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.03.033 * Corresponding author. Tel.: +1 412 396 1847; fax: +1 412 396 4660. E-mail address: flahertyp@duq.edu (P.T. Flaherty). Figure 1. The MEK5 signaling cascade. Bioorganic & Medicinal Chemistry Letters 20 (2010) 2892–2896 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl