Small Molecule Inhibitors of Interferon‐Induced JAK‐STAT Signalling

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.Interferons (IFNs) are pleiotropic cytokines that play key roles in immunity for host defence against pathogens and tumour control. [1] IFN binding to the type I and type II IFN receptors triggers a downstream activation of the canonical Janus Kinase (JAK)-Signal Transducer and Activator of Transcription protein (STAT) signalling pathway, and its dysregulation has been involved in the pathogenesis of autoimmune diseases, inflammatory diseases and cancer. [2]

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“…1a). Moreover, we recently showed that SMIFH2 and its derived compounds can directly inhibit IFN-γ activity in the extracellular medium (Thoidingjam et al, 2022). To eliminate extracellular SMIFH2 before cytokine addition, we added a PBS washing step (SMI-WASH) prior to IFN-γ stimulation (Fig.…”

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“…A sophisticated understanding of JAK-STAT signaling has many insights into the development of novel drugs. [548][549][550] However, many challenges remain for improving target selectivity in JAK-STAT signaling, and exploration of the long-term safety of the developed agents is still required. Each JAK inhibitor impedes the combination of a JAK enzyme with ATP through the highly selective ATP-binding pocket.…”

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“…The JAK/STAT signaling pathway constitutes one of the major cell signaling hubs in cellular homeostasis. This evolutionarily conserved pathway can be activated by numerous hormones, growth factors, interferons (IFNs), interleukins (ILs), and colony-stimulating factors and is involved in the control of a variety of processes, including apoptosis, survival, and inflammation [ 173 , 174 ]. In the traditional JAK/STAT pathway, the interaction between the ligand and its receptor triggers the dimerization and transphosphorylation of the second.…”