Small Molecule Inhibitors of Interferon-Induced JAK-STAT Signalling

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2022 May 25

PMID 35612562

Authors

Leishemba K Thoidingjam

Cedric M Blouin

Christine Gaillet

Aurelien Brion

Stephanie Solier

Supaporn Niyomchon

Ahmed El Marjou

Sara Mouasni

Fernando E Sepulveda

Genevieve de Saint Basile

Christophe Lamaze

Raphael Rodriguez

Affiliations

Soon will be listed here.

Abstract

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.

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

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