American Chemical Society
Browse

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor

Download (3.43 MB)
journal contribution
posted on 2022-04-25, 23:43 authored by Duncan C. Miller, Tristan Reuillon, Lauren Molyneux, Timothy Blackburn, Simon J. Cook, Noel Edwards, Jane A. Endicott, Bernard T. Golding, Roger J. Griffin, Ian Hardcastle, Suzannah J. Harnor, Amy Heptinstall, Pamela Lochhead, Mathew P. Martin, Nick C. Martin, Stephanie Myers, David R. Newell, Richard A. Noble, Nicole Phillips, Laurent Rigoreau, Huw Thomas, Julie A. Tucker, Lan-Zhen Wang, Michael J. Waring, Ai-Ching Wong, Stephen R. Wedge, Martin E. M. Noble, Celine Cano
The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

History