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

  • Eur J Med Chem. 2019 Sep 15;178:530-543. doi: 10.1016/j.ejmech.2019.05.057.
Stephanie M Myers  1 ,  Duncan C Miller  1 ,  Lauren Molyneux  1 ,  Mercedes Arasta  2 ,  Ruth H Bawn  1 ,  Timothy J Blackburn  1 ,  Simon J Cook  3 ,  Noel Edwards  2 ,  Jane A Endicott  2 ,  Bernard T Golding  1 ,  Roger J Griffin  1 ,  Tim Hammonds  4 ,  Ian R Hardcastle  1 ,  Suzannah J Harnor  1 ,  Amy B Heptinstall  1 ,  Pamela A Lochhead  3 ,  Mathew P Martin  2 ,  Nick C Martin  1 ,  David R Newell  2 ,  Paul J Owen  4 ,  Leon C Pang  4 ,  Tristan Reuillon  1 ,  Laurent J M Rigoreau  5 ,  Huw D Thomas  2 ,  Julie A Tucker  2 ,  Lan-Zhen Wang  2 ,  Ai-Ching Wong  4 ,  Martin E M Noble  6 ,  Stephen R Wedge  7 ,  Celine Cano  8
Affiliations
  • 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: [email protected].
  • 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: [email protected].
  • 8. Newcastle Drug Discovery, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK. Electronic address: [email protected].
PMID: 31212132 DOI: 10.1016/j.ejmech.2019.05.057
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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