Background/Purpose: The family of Janus kinases (JAK1, JAK2, JAK3, TYK2) mediate signal transduction from cytokine receptors through phosphorylation and activation of intracellular signaling pathways and transcription factors. Small molecule antagonists of JAKs (jakinibs) have been developed with varying potencies and selectivities for the use in malignancies and immune regulation. There is growing recognition for the effectiveness of jakinibs in some forms of autoimmunity of the skeletal muscle like dermatomyositis, but which of these drugs is most effective is unknown.

Methods: We assayed a library of 48 commercially available jakinibs for their ability to inhibit the IFN-β or IFN-γ – major histocompatibility complex (MHC) class I pathway in human myoblasts genome-engineered to fuse a pro-luminescent HiBiT peptide to endogenous MHC class I gene HLA-B*08:01. Results from the top actives were confirmed by RT-qPCR and phospho-STAT1 flow cytometry in primary human myoblasts.

Results: The most potent and effective compounds for blocking IFN-β signaling over 24 hrs by the MHC class I-HiBit assay were deucravacitinib (TYK2 inhibitor, FDA approved) with an IC50 of 72 nM and upadacitinib (JAK1/2 inhibitor, FDA approved) with an IC50 of 330 nM and. Deucravacitinib was the most selective at inhibiting IFN-β over IFN-γ.

Conclusion: These highly active jakinibs, like deucravacitinib and upadacitinib, warrant further clinical evaluation to show their safety and efficacy in myositis patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparison-of-janus-kinase-inhibitors-to-block-the-type-i-and-ii-interferon-pathways-in-human-myoblasts/