ERK5-IN-2

Description: ERK5-IN-2 is a novel, potent, orally bioavailable, sub-micromolar, and selective ERK5 inhibitor with selectivity over p38alpha and BRD4. It has IC50s of 0.82 uM, 3 uM for ERK5 and ERK5 MEF2D, respectively. ERK5-IN-2 suppresses both tumor xenograft growth and basic fibroblast growth factor (bFGF) driven Matrigel plug angiogenesis. 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 such as ERK5-IN-2 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 p38alpha MAP kinase. Truncation of the N-substituent marginally enhanced potency (?3-fold) against ERK5, but importantly attenuated inhibition of p38alpha. 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?uM for ERK5; IC50?> ?120?uM for p38alpha). 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.

References: Eur J Med Chem. 2019 May 25; 178:530-543.