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

  • J Med Chem. 2022 May 12;65(9):6513-6540. doi: 10.1021/acs.jmedchem.1c01756.
Duncan C Miller  1 ,  Tristan Reuillon  1 ,  Lauren Molyneux  1 ,  Timothy Blackburn  1 ,  Simon J Cook  2 ,  Noel Edwards  3 ,  Jane A Endicott  3 ,  Bernard T Golding  1 ,  Roger J Griffin  1 ,  Ian Hardcastle  1 ,  Suzannah J Harnor  1 ,  Amy Heptinstall  1 ,  Pamela Lochhead  2 ,  Mathew P Martin  3 ,  Nick C Martin  1 ,  Stephanie Myers  1 ,  David R Newell  3 ,  Richard A Noble  3 ,  Nicole Phillips  3 ,  Laurent Rigoreau  4 ,  Huw Thomas  3 ,  Julie A Tucker  3 ,  Lan-Zhen Wang  3 ,  Michael J Waring  1 ,  Ai-Ching Wong  5 ,  Stephen R Wedge  3 ,  Martin E M Noble  3 ,  Celine Cano  1
Affiliations
  • 1. Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, School of Natural and Environmental Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
  • 2. Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 3. Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
  • 4. Cancer Research UK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Campus, Babraham, Cambridgeshire CB22 3AT, U.K.
  • 5. Cancer Research UK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, U.K.
PMID: 35468293 DOI: 10.1021/acs.jmedchem.1c01756
Abstract

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.

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