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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.

Research paper by Duy D Nguyen, Clara C Lemos, Lars L Wortmann, Knut K Eis, Simon J SJ Holton, Ulf U Boemer, Dieter D Moosmayer, Uwe U Eberspaecher, Joerg J Weiske, Christian C Lechner, Stefan S Prechtl, Detlev D Suelzle, Franziska F Siegel, Florian F Prinz, Ralf R Lesche, et al.

Indexed on: 20 Dec '18Published on: 20 Dec '18Published in: Journal of Medicinal Chemistry



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 reported the identification of a highly potent and selective ERK5 inhibitor BAY-855 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.