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Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid β (Aβ) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associated protein in neurons and stabilizes microtubules (MTs). Cyclin dependent kinase 5 (CDK5), when activated by the regulatory binding protein p25, phosphorylates tau at a number of proline-directed serine/threonine residues, resulting in formation of phosphorylated tau as paired helical filaments (PHFs) then in subsequent deposition of PHFs as NFTs. Beginning with the structure of Roscovitine, a moderately selective CDK5 inhibitor, we sought to conduct structural modifications to increase inhibitory potency of CDK5 and increase selectivity over a similar enzyme, cyclin dependent kinase 2 (CDK2). The design, synthesis, and testing of a series of 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles is presented. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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 signaling cascade in cultured HEK cells has identified compounds that can inhibit MEK5 phosphorylation of ERK5; observed biological activity is dependent on chemical variation. [Copyright &y& Elsevier]