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
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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