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

Lookup NU author(s): Stephanie Myers, Duncan MillerORCiD, Dr Lauren Molyneux, Dr Mercedeh Arasta, Dr Ruth Bawn, Dr Tim Blackburn, Dr Noel Edwards, Professor Jane Endicott, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Ian HardcastleORCiD, Dr Suzannah HarnorORCiD, Amy Heptinstall, Dr Mathew Martin, Nick Martin, Professor Herbie Newell, Tristan Reuillon, Dr Laurent Rigoreau, Huw ThomasORCiD, Julie Tucker, Lan Wang, Professor Martin NobleORCiD, Professor Steve Wedge, Dr Celine CanoORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2019 Elsevier Masson SASExtracellular 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.

Publication metadata

Author(s): Myers SM, Miller DC, Molyneux L, Arasta M, Bawn RH, Blackburn TJ, Cook SJ, Edwards N, Endicott JA, Golding BT, Griffin RJ, Hammonds T, Hardcastle IR, Harnor SJ, Heptinstall AB, Lochhead PA, Martin MP, Martin NC, Newell DR, Owen PJ, Pang LC, Reuillon T, Rigoreau LJM, Thomas HD, Tucker JA, Wang L-Z, Wong A-C, Noble MEM, Wedge SR, Cano C

Publication type: Article

Publication status: Published

Journal: European Journal of Medicinal Chemistry

Year: 2019

Volume: 178

Pages: 530-543

Print publication date: 15/09/2019

Online publication date: 25/05/2019

Acceptance date: 20/05/2019

Date deposited: 22/07/2019

ISSN (print): 0223-5234

ISSN (electronic): 1768-3254

Publisher: Elsevier Masson SAS


DOI: 10.1016/j.ejmech.2019.05.057


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Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)
MR/K007580/1Medical Research Council (MRC)