2. Academic Validation
  3. Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4

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

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: 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.
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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