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FM-381 is a potent covalent reversible inhibitor of JAK3 targeting the unique Cys909. FM-381 has an IC50 of 127 pM for JAK3, with 410, 2700 and 3600-fold selectivity over JAK1, JAK2 and TYK2, respectively.

FM-381 is a highly potent and JAK3-selective janus kinase (JAK) inhibitor (IC50 = 127 pM/JAK352 nM/JAK1346 nM/JAK2459 nM/TYK2 by radiometric assay; [ATP] = 10 μM) th at targets JAK3 gatekeeper (GK) Cys909 for a reversible covalent interactionexhibiting much reduced or little potency against a panel of 409 other kinases. FM-381 is >3-fold more potent than the JAK1/3 inhibitor Tofacitinib (IC50 = 292 pM/JAK3496 pM/JAK12.2 nM/JAK28.9 nM/TYK2 by radiometric assay; [ATP] = 10 μM) in blocking JAK1/JAK3-mediated STAT5 phosphorylation in human CD4+ T-cells upon IL-2 stimulation (ECmax ∼100 nM with FM-381)while being ineffective (up to 1 μM) against JAK3-independent STAT1/3 phosphorylation following IL-6 or TNFα stimulation. For characterization details of FM-381please visit the FM-381 probe summary on the Structural Genomics Consortium (SGC) website.

FM-479 is the negative control

JAK3: 127 pM (IC₅₀)

[1] Forster M, et al. Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket. Cell Chem Biol. 2016 Nov 17;23(11):1335-1340. DOI:10.1016/j.chembiol.2016.10.008