Discovery and Characterization of the Potent and Highly Selective (Piperidin-4-yl)pyrido[3,2- d]pyrimidine Based in Vitro Probe BAY-885 for the Kinase ERK5

  • J Med Chem. 2019 Jan 24;62(2):928-940. doi: 10.1021/acs.jmedchem.8b01606.
Duy Nguyen  1 ,  Clara Lemos  1 ,  Lars Wortmann  1 ,  Knut Eis  1 ,  Simon J Holton  1 ,  Ulf Boemer  1 ,  Dieter Moosmayer  1 ,  Uwe Eberspaecher  1 ,  Joerg Weiske  1 ,  Christian Lechner  1 ,  Stefan Prechtl  1 ,  Detlev Suelzle  1 ,  Franziska Siegel  1 ,  Florian Prinz  1 ,  Ralf Lesche  1 ,  Barbara Nicke  1 ,  Katrin Nowak-Reppel  1 ,  Herbert Himmel  1 ,  Dominik Mumberg  1 ,  Franz von Nussbaum  1 ,  Carl F Nising  1 ,  Marcus Bauser  1 ,  Andrea Haegebarth  1
Affiliations
  • 1. Research & Development, Pharmaceuticals , Bayer AG , 13353 Berlin , Germany.
PMID: 30563338 DOI: 10.1021/acs.jmedchem.8b01606
Abstract

The availability of a chemical probe to study the role of a specific domain of a protein in a concentration- and time-dependent manner is of high value. Herein, we report the identification of a highly potent and selective ERK5 Inhibitor BAY-885 by high-throughput screening and subsequent structure-based optimization. ERK5 is a key integrator of cellular signal transduction, and it has been shown to play a role in various cellular processes such as proliferation, differentiation, Apoptosis, and cell survival. We could demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, which is in contrast to the results obtained by RNAi technology.

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