Comparison of Janus kinase inhibitors to block the type I interferon pathway in human skeletal muscle cells

Abstract

The family of Janus kinases (JAK1, JAK2, JAK3, TYK2) mediate signal transduction from cytokine receptors by phosphorylation and activation of intracellular signaling pathways and transcription factors. Small molecule antagonists of JAKs (Jakinibs) have been developed with varying selectivity for the use in malignancies and immune regulation. There is growing recognition of the effectiveness of jakinibs in autoimmunity of the skeletal muscle called myositis, but which of these drugs is most effective is unknown. We have assayed a library of 48 jakinibs for their ability to inhibit the JAK1/TYK2-dependent type I interferon (IFN) - major histocompatibility complex (MHC) class I pathway using human skeletal muscle cells genome-engineered to fuse a pro-luminescent HiBiT peptide to endogenous MHC class I. The most effective compounds were upadacitinib (JAK1/2 inhibitor, FDA approved) and deucravacitinib (TYK2 inhibitor, phase III). These active jakinibs warrant further clinical evaluation to show their safety and efficacy in patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/430317v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1be9551org.highwire.dtl.DTLVardef@13d1882org.highwire.dtl.DTLVardef@1414fborg.highwire.dtl.DTLVardef@6d8780_HPS_FORMAT_FIGEXP M_FIG C_FIG