Small Molecule Inhibitors of Interferon-Induced JAK-STAT Signalling.

Autor:	Thoidingjam LK; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Blouin CM; Membrane Mechanics and Dynamics of Intracellular Signalling, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Gaillet C; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Brion A; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Solier S; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Niyomchon S; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., El Marjou A; Protein Expression and Purification Core Facility, Institut Curie, PSL Research University, UMR 144 CNRS, 75005, Paris, France., Mouasni S; Molecular basis of altered immune homeostasis laboratory, Université de Paris, Imagine Institute, INSERM UMR 1163, 75015, Paris, France., Sepulveda FE; Molecular basis of altered immune homeostasis laboratory, Université de Paris, Imagine Institute, INSERM UMR 1163, 75015, Paris, France., de Saint Basile G; Molecular basis of altered immune homeostasis laboratory, Université de Paris, Imagine Institute, INSERM UMR 1163, 75015, Paris, France.; Centre d'Etude des Déficits Immunitaires, AP-HP, Hôpital Necker-Enfants Malades, Paris, France., Lamaze C; Membrane Mechanics and Dynamics of Intracellular Signalling, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France., Rodriguez R; Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France.
Jazyk:	angličtina
Zdroj:	Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2022 Aug 08; Vol. 61 (32), pp. e202205231. Date of Electronic Publication: 2022 Jun 14.
DOI:	10.1002/anie.202205231
Abstrakt:	Interferons (IFN) are cytokines which, upon binding to cell surface receptors, trigger a series of downstream biochemical events including Janus Kinase (JAK) activation, phosphorylation of Signal Transducer and Activator of Transcription protein (STAT), translocation of pSTAT to the nucleus and transcriptional activation. Dysregulated IFN signalling has been linked to cancer progression and auto-immune diseases. Here, we report the serendipitous discovery of a small molecule that blocks IFNγ activation of JAK-STAT signalling. Further lead optimisation gave rise to a potent and more selective analogue that exerts its activity by a mechanism consistent with direct IFNγ targeting in vitro, which reduces bleeding in model of haemorrhagic colitis in vivo. This first-in-class small molecule also inhibits type I and III IFN-induced STAT phosphorylation in vitro. Our work provides the basis for the development of pan-IFN inhibitory drugs. (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze:	MEDLINE
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