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

Lookup NU author(s): Duncan MillerORCiD, Tristan Reuillon, Dr Lauren Molyneux, Dr Tim Blackburn, Dr Noel Edwards, Professor Jane Endicott, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Ian HardcastleORCiD, Dr Suzannah HarnorORCiD, Amy Heptinstall, Dr Mathew Martin, Nick Martin, Stephanie Myers, Dr Richard NobleORCiD, Nicole Phillips, Huw ThomasORCiD, Julie Tucker, Lan Wang, Professor Mike Waring, Professor Steve Wedge, Professor Martin NobleORCiD, Dr Celine CanoORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Authors. Published by American Chemical Society. 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.

Publication metadata

Author(s): Miller DC, Reuillon T, Molyneux L, Blackburn T, Cook SJ, Edwards N, Endicott JA, Golding BT, Griffin RJ, Hardcastle I, Harnor SJ, Heptinstall A, Lochhead P, Martin MP, Martin NC, Myers S, Newell DR, Noble RA, Phillips N, Rigoreau L, Thomas H, Tucker JA, Wang L-Z, Waring MJ, Wong A-C, Wedge SR, Noble MEM, Cano C

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2022

Volume: 65

Issue: 9

Pages: 6513-6540

Print publication date: 12/05/2022

Online publication date: 25/04/2021

Acceptance date: 02/04/2018

Date deposited: 17/05/2022

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.1c01756

PubMed id: 35468293


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Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)
MR/K007580/1Medical Research Council (MRC)