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

Miller, Duncan C, Reuillon, Tristan, Molyneux, Lauren, Blackburn, Timothy, Cook, Simon J, Edwards, Noel, Endicott, Jane A, Golding, Bernard T, Griffin, Roger J, Hardcastle, Ian, Harnor, Suzannah J, Heptinstall, Amy, Lochhead, Pamela, Martin, Mathew P, Martin, Nick C, Myers, Stephanie, Newell, David R, Noble, Richard A, Phillips, Nicole, Rigoreau, Laurent, Thomas, Huw, Tucker, Julie A, Wang, Lan-Zhen, Waring, Michael J, Wong, Ai-Ching, Wedge, Stephen R, Noble, Martin E and Cano, Celine (2022) Parallel Optimisation of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor. Journal of Medicinal Chemistry, 65 (9). pp. 6513-6540. ISSN 0022-2623

Item Type: Article


The non-classical 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, 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 optimisation of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic centre, which suffered from poor oral bioavailability. Parallel optimisation of potency and in vitro pharmacokinetic parameters led to the identification of a non-basic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

acs.jmedchem.1c01756.pdf - Published Version
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More Information

Depositing User: Stephanie Myers


Item ID: 14709
Identification Number: 10.1021
ISSN: 0022-2623
Official URL:

Users with ORCIDS

ORCID for Stephanie Myers: ORCID iD

Catalogue record

Date Deposited: 15 May 2023 10:02
Last Modified: 11 Jul 2023 08:02


Author: Stephanie Myers ORCID iD
Author: Duncan C Miller
Author: Tristan Reuillon
Author: Lauren Molyneux
Author: Timothy Blackburn
Author: Simon J Cook
Author: Noel Edwards
Author: Jane A Endicott
Author: Bernard T Golding
Author: Roger J Griffin
Author: Ian Hardcastle
Author: Suzannah J Harnor
Author: Amy Heptinstall
Author: Pamela Lochhead
Author: Mathew P Martin
Author: Nick C Martin
Author: David R Newell
Author: Richard A Noble
Author: Nicole Phillips
Author: Laurent Rigoreau
Author: Huw Thomas
Author: Julie A Tucker
Author: Lan-Zhen Wang
Author: Michael J Waring
Author: Ai-Ching Wong
Author: Stephen R Wedge
Author: Martin E Noble
Author: Celine Cano

University Divisions

Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Chemistry

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