2. Academic Validation
  3. Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor

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

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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