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.
Duy NguyenClara LemosLars WortmannKnut EisSimon J HoltonUlf BoemerDieter MoosmayerUwe EberspaecherJoerg WeiskeChristian LechnerStefan PrechtlDetlev SuelzleFranziska SiegelFlorian PrinzRalf LescheBarbara NickeKatrin Nowak-ReppelHerbert HimmelDominik MumbergFranz von NussbaumCarl F NisingMarcus BauserAndrea HaegebarthPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- signaling pathway
- small molecule
- pi k akt
- cell proliferation
- cell cycle arrest
- protein protein
- living cells
- quantum dots
- oxidative stress
- gene expression
- tyrosine kinase
- transcription factor
- magnetic resonance
- high throughput
- endoplasmic reticulum stress
- cell therapy
- cell death
- heat shock
- heat stress
- fluorescent probe
- heat shock protein