Discovery of a highly selective JAK3 inhibitor for the treatment of inflammatory bowel disease
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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We developed Compound 15 as a novel covalent JAK3 inhibitor with excellent subtype selectivity.
Compound 15 alleviates intestinal inflammation in zebrafish models without thrombocyte depletion.
This low-toxicity compound serves as a promising IBD therapeutic candidate.
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ABSTRACT
Janus kinase 3 (JAK3) is a promising target for inflammatory bowel disease (IBD). However, the clinical utility of currently approved pan-JAK inhibitors is severely limited by off-target JAK2 inhibition, which is associated with serious side effects such as thrombocytopenia and thrombosis. Herein, a series of pteridine-7(8H)-one derivatives were designed as selective covalent JAK3 inhibitors. Among them, compound 15 exhibited exceptional inhibitory activity against JAK3 (IC50 = 0.49 ± 0.05 nM) and a remarkable selectivity profile (> 2000-fold over JAK1, JAK2 and TYK2). Notably, compound 15 significantly attenuated intestinal inflammation in a zebrafish IBD model. Moreover, it showed no risk of inducing thrombocytopenia even at high doses, contrasting with the adverse effects observed with tofacitinib. Its superior selectivity profile effectively avoids JAK2-mediated off-target effects, positioning compound 15 as a highly promising, low-toxicity covalent inhibitor for the treatment of IBD.-
Keywords:
- JAK3 /
- Inhibitor /
- Selectivity /
- IBD.
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REFERENCES
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Cite this article:
Wang C., Huang C., Wu Y., et al. (2026). Discovery of a highly selective JAK3 inhibitor for the treatment of inflammatory bowel disease. The Innovation Drug Discovery 1:100029. https://doi.org/10.59717/j.xinn-drugdisc.2026.100029
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Wang C., Huang C., Wu Y., et al. (2026). Discovery of a highly selective JAK3 inhibitor for the treatment of inflammatory bowel disease. The Innovation Drug Discovery 1:100029. https://doi.org/10.59717/j.xinn-drugdisc.2026.100029
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Content
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Figure 1.
The structures and activities of (A) non-selective JAK inhibitors and (B) selective JAK3 inhibitors
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Figure 2.
Structure-based optimization of ZW-032 for enhanced JAK3 inhibitory potency
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Figure 1.
Synthesis of compounds 6-23α. αReagents and conditions
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Figure 2.
Synthesis of compounds 24-28α. αReagents and conditions
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Figure 3.
Synthesis of compounds 29-31α. αReagents and conditions
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Figure 3.
The binding mode of compound 15 into the JAK3 kinase domain. The hydrogen bond interactions are represented by yellow dotted lines
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Figure 4.
Kinase selectivity profile of compound 15 against 468 kinases
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Figure 5.
Effects of compound 15 in a zebrafish model of IBD
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Figure 6.
Assessment of compound 15 and tofacitinib on platelet counts in zebrafish
