title: Inhibitor-based affinity probes for the investigation of JAK signaling pathways.
abstract: The Janus Kinase (JAK) signaling pathway plays a key role for many cellular processes and has recently been correlated with neuronal disorders. In order to understand new links of JAK family members with other signaling pathways, chemical proteomics tools with broad kinase coverage are desirable. A probe that shows outstanding kinase selectivity and allows for the enrichment of up to 133 kinases including many mitogen activated kinase (MAPK) members and JAK kinases has been developed. Furthermore, this probe was applied to establish the selectivity profile of the JAK1/2 inhibitor momelotinib that is currently evaluated in clinical phase 3 studies. These results render this probe a valuable tool for the investigation of JAK and JAK related signaling pathways and the selectivity profiling of kinase inhibitors.
authors.affiliation: Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Höfener
authors.affiliation: Chair of Proteomics and Bioanalytics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
authors.forename: Fiona
authors.initials: F
authors.lastname: Pachl
authors.affiliation: Chair of Proteomics and Bioanalytics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.|Center for Integrated Protein Science Munich, Freising, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.affiliation: Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Sewald
mesh_terms: D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062105:Molecular Docking Simulation; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000378:metabolism
chemical_list: D001549:Benzamides; D015335:Molecular Probes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human
keywords: Animal proteomics; Chemical proteomics; JAK-signaling; Kinase; Mass spectrometry; Selectivity profiling