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

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  • Stephanie M. Myers
  • Duncan C. Miller
  • Lauren Molyneux
  • Mercedes Arasta
  • Ruth H. Bawn
  • Timothy J. Blackburn
  • Simon J. Cook
  • Noel Edwards
  • Jane A. Endicott
  • Bernard T. Golding
  • Roger J. Griffin
  • Tim Hammonds
  • Ian R. Hardcastle
  • Suzannah J. Harnor
  • Amy B. Heptinstall
  • Pamela A. Lochhead
  • Mathew P. Martin
  • Nick C. Martin
  • David R. Newell
  • Paul J. Owen
  • Leon C. Pang
  • Tristan Reuillon
  • Laurent J.M. Rigoreau
  • Huw D. Thomas
  • Lan-Zhen Wang
  • Ai-Ching Wong
  • Martin E.M. Noble
  • Stephen R. Wedge
  • Celine Cano


Publication details

JournalEuropean Journal of Medicinal Chemistry
DateAccepted/In press - 20 May 2019
DateE-pub ahead of print - 25 May 2019
DatePublished (current) - 15 Sep 2019
Number of pages14
Pages (from-to)530-543
Early online date25/05/19
Original languageEnglish


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 IC 50 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 (IC 50 0.82 μM for ERK5; IC 50 > 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.

Bibliographical note

© 2019 Elsevier Masson SAS. All rights reserved. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

    Research areas

  • BMK1, Bioavailable, ERK5, Extracellular regulated kinase 5, Kinase, Pyrrole carboxamide

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