Chemical Biology Laboratory, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France.
Membrane Mechanics and Dynamics of Intracellular Signalling, Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, 75005, Paris, France.
Angew Chem Int Ed Engl. 2022 Aug 8;61(32):e202205231. doi: 10.1002/anie.202205231. Epub 2022 Jun 14.
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.
干扰素 (IFN) 是细胞因子，与细胞表面受体结合后，触发一系列下游生化事件，包括 Janus 激酶 (JAK) 的激活、信号转导和转录激活因子 (STAT) 的磷酸化、pSTAT 向细胞核的易位和转录激活。失调的 IFN 信号与癌症进展和自身免疫性疾病有关。在这里，我们报告了一种小分子阻断 IFNγ 激活 JAK-STAT 信号的偶然发现。进一步的先导优化产生了一种更有效和更具选择性的类似物，其活性机制与体外直接针对 IFNγ 的机制一致，这在体内出血性结肠炎模型中减少了出血。这种首创的小分子还抑制体外 I 型和 III 型 IFN 诱导的 STAT 磷酸化。我们的工作为开发泛 IFN 抑制药物奠定了基础。
