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

DOI: 10.1016/j.ejmech.2019.05.057

Authors: Stephanie Myers (Northern Institute for Cancer Research, Newcastle University) , Duncan C. Miller (Northern Institute for Cancer Research, Newcastle University) , Lauren Molyneux (Northern Institute for Cancer Research, Newcastle University) , Mercedes Arasta (Northern Institute for Cancer Research, Newcastle University) , Ruth H. Bawn (Northern Institute for Cancer Research, Newcastle University) , Timothy Blackburn (Northern Institute for Cancer Research, Newcastle University) , Simon J. Cook (The Babraham Institute) , Noel Edwards (Northern Institute for Cancer Research, Newcastle University) , Jane A. Endicott (Northern Institute for Cancer Research, Newcastle University) , Bernard T. Golding (Northern Institute for Cancer Research, Newcastle University) , Roger J. Griffin (Northern Institute for Cancer Research, Newcastle University) , Tim Hammonds (Cancer Research UK Therapeutic Discovery Laboratories) , Ian R. Hardcastle (Northern Institute for Cancer Research, Newcastle University) , Suzannah J. Harnor (Northern Institute for Cancer Research, Newcastle University) , Amy Heptinstall (Northern Institute for Cancer Research, Newcastle University) , Pamela Lochhead (The Babraham Institute) , Mathew P. Martin (Northern Institute for Cancer Research, Newcastle University) , Nick C. Martin (Northern Institute for Cancer Research, Newcastle University) , David R. Newell (Northern Institute for Cancer Research, Newcastle University) , Paul J. Owen (Cancer Research UK Therapeutic Discovery Laboratories) , Leon C. Pang (Cancer Research UK Therapeutic Discovery Laboratories) , Tristan Reuillon (Northern Institute for Cancer Research, Newcastle University) , Laurent J. M. Rigoreau (Cancer Research UK Therapeutic Discovery Laboratories) , Huw Thomas (Northern Institute for Cancer Research, Newcastle University) , Julie A. Tucker (Northern Institute for Cancer Research, Newcastle University) , Lan-Zhen Wang (Northern Institute for Cancer Research, Newcastle University) , Ai-Ching Wong (Cancer Research UK Therapeutic Discovery Laboratories) , Martin E. M. Noble (Northern Institute for Cancer Research, Newcastle University) , Stephen R. Wedge (Northern Institute for Cancer Research, Newcastle University) , Celine Cano (Northern Institute for Cancer Research, Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 9948 , 13587

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.

Journal Keywords: ERK5; Extracellular regulated kinase 5; BMK1; Kinase; Bioavailable; Pyrrole carboxamide

Subject Areas: Chemistry, Medicine, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 29/05/2019 09:04

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)