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RESEARCH PRODUCT
Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach
Iñaki TuñónSanzio CandelettiPatrizia RomualdiIrene AlessandriniAndrea CavalliAndrea CavalliSerena StamatakosMatteo MasettiRiccardo ZanniMaurizio RecanatiniRiccardo OcelloLaura RulloMaria Galvez-llompartMaria Galvez-llompartsubject
General Chemical EngineeringTransducersBioinformatics and computational biology Inhibitors Inhibition Peptides and proteins MoleculesLibrary and Information SciencesLigands01 natural sciencesstatArticleProinflammatory cytokine0103 physical sciencesProtein Kinase InhibitorsJanus KinasesTofacitinib010304 chemical physicsActivator (genetics)ChemistryJAK-STAT signaling pathwayGeneral Chemistry0104 chemical sciencesComputer Science ApplicationsCell biology010404 medicinal & biomolecular chemistryDocking (molecular)Signal transductionJanus kinaseSignal Transductiondescription
Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK-signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro. Two hit compounds with a novel chemical scaffold, 4 (IC50 = 0.81 μM) and 7 (IC50 = 0.64 μM), showed promising results when compared with the reference drug Tofacitinib (IC50 = 0.031 μM).
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-05-17 | Journal of Chemical Information and Modeling |