Small Molecule Inhibitors of Interferon‐Induced JAK‐STAT Signalling

Interferons (IFN) are cytokines which, upon binding to cell surface receptors, trigger a series of downstream biochemical events including Janus Kinase (JAK) activation, phosphorylation Signal Transducer and Activator Transcription protein (STAT), translocation pSTAT the nucleus transcriptional activation. Dysregulated IFN signalling has been linked cancer progression auto-immune diseases. Here, we report serendipitous discovery small molecule that blocks IFNγ activation JAK-STAT signalling. Further lead optimisation gave rise potent more selective analogue exerts its activity by mechanism consistent with direct targeting in vitro, which reduces bleeding model haemorrhagic colitis vivo. This first-in-class also inhibits type I III IFN-induced STAT vitro. Our work provides basis for development pan-IFN inhibitory drugs.