Identification of a Novel Orally Bioavailable ERK5 Inhibitor with Selectivity over p38α and BRD4

Myers, Stephanie (2019) Identification of a Novel Orally Bioavailable ERK5 Inhibitor with Selectivity over p38α and BRD4. European Journal of Medicinal Chemistry. ISSN 02235234 (In Press)

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Abstract

Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (~ 3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 >120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.

Item Type: Article
Subjects: Sciences > Chemistry
Sciences > Pharmacy and Pharmacology
Divisions: Faculty of Health Sciences and Wellbeing
Depositing User: Stephanie Myers
Date Deposited: 28 May 2019 11:52
Last Modified: 28 May 2019 12:00
URI: http://sure.sunderland.ac.uk/id/eprint/10813

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