Tucker, Julie Ann orcid.org/0000-0002-6119-676X, Myers, Stephanie M., Miller, Duncan C. et al. (27 more authors) (2019) Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4. European Journal of Medicinal Chemistry. pp. 530-543. ISSN 0223-5234
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 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 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. |
Keywords: | BMK1,Bioavailable,ERK5,Extracellular regulated kinase 5,Kinase,Pyrrole carboxamide |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 03 Jul 2019 09:30 |
Last Modified: | 22 Jan 2025 00:12 |
Published Version: | https://doi.org/10.1016/j.ejmech.2019.05.057 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1016/j.ejmech.2019.05.057 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:148098 |
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Description: ERK5LeadIDPaper EurJMedChem 2019-04-29
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