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Eur J Med Chem. 2019 May 25;178:530-543. doi: 10.1016/j.ejmech.2019.05.057. [Epub ahead of print]

Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4.

Author information

1
Newcastle Drug Discovery, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
2
Newcastle Drug Discovery, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
3
Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
4
Cancer Research UK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, 2 Royal College Street, London, NW1 0NH, UK.
5
Cancer Research UK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Campus, Babraham, Cambridgeshire, CB22 3AT, UK.
6
Newcastle Drug Discovery, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK. Electronic address: martin.noble@ncl.ac.uk.
7
Newcastle Drug Discovery, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK. Electronic address: steve.wedge@ncl.ac.uk.
8
Newcastle Drug Discovery, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK. Electronic address: celine.cano@ncl.ac.uk.

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.

KEYWORDS:

BMK1; Bioavailable; ERK5; Extracellular regulated kinase 5; Kinase; Pyrrole carboxamide

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