Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4
Autor: | Simon J. Cook, Mathew P. Martin, Julie A. Tucker, Miller Duncan Charles, Timothy J. Blackburn, Stephanie M. Myers, Ai-Ching Wong, Nick C. Martin, Mercedes Arasta, Martin E.M. Noble, Huw D. Thomas, Ruth H. Bawn, Lan-Zhen Wang, Noel Edwards, Pamela A. Lochhead, Celine Cano, Suzannah J. Harnor, Tristan Reuillon, Laurent Rigoreau, Lauren Molyneux, Roger J. Griffin, David R. Newell, Bernard T. Golding, Tim Hammonds, Amy B. Heptinstall, P.J. Owen, Stephen R. Wedge, Ian R. Hardcastle, Leon Pang, Jane A. Endicott |
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Přispěvatelé: | Myers, Stephanie, Miller, Duncan, Molyneux, Lauren, Arasta, Mercedes, Bawn, Ruth, Blackburn, Timothy, Cook, Simon, Edwards, Noel, Endicott, Jane, Golding, Bernard, Griffin, Roger, Hammonds, Tim, Hardcastle, Ian, Harnor, Suzannah, Heptinstall, Amy, Lochhead, Pamela, Martin, Mathew, Martin, Nick, Newell, Herbie, Owen, Paul, Pang, Leon, Reuillon, Tristan, Rigoreau, Laurent, Thomas, Huw, Tucker, Julie, Wang, Lan-Zhen, Wong, Ai-Ching, Noble, Martin, Wedge, Stephen, Cano, Celine |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Angiogenesis
High-throughput screening Motility Administration Oral Biological Availability Mice Nude Antineoplastic Agents Cell Cycle Proteins 01 natural sciences Mitogen-Activated Protein Kinase 14 03 medical and health sciences Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery Extracellular Animals Humans IC50 Protein Kinase Inhibitors Mitogen-Activated Protein Kinase 7 030304 developmental biology Cell Proliferation Pharmacology sub_chemistry 0303 health sciences biology sub_pharmacyandpharmacology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Kinase Organic Chemistry Nuclear Proteins General Medicine Neoplasms Experimental 0104 chemical sciences Endothelial stem cell Biochemistry Mitogen-activated protein kinase biology.protein Female Drug Screening Assays Antitumor Transcription Factors |
ISSN: | 0223-5234 |
Popis: | 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. |
Databáze: | OpenAIRE |
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