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You need too inhibit your JAKS all research shows this, BMS bucking the trend with their highly selective TYK2 more selective than ours, stay away from selective JAK2 (issues) this article is saying you need a bit of JAK2 to completely phosphorylate IL12-23 as the TYK2 inhibits the same pathways IL12-23 anyway without side effects, so good at being a selective TYK2 but dual inhibiting molecules are better, I guess it all comes down to the right balance of selectively between JAKS/TYK2!
What does all this mean ?
These highly selective TYK2 compounds were less potent in inhibiting IL-23–induced phospho-STAT3 than in inhibiting the TYK2 reference cell assay (i.e., lying above the red unity line in and more potent in inhibiting IL-23–induced phospho-STAT3 than in inhibiting the JAK2 reference cell assay (i.e., lying below the red unity line in. These results indicate that under conditions of strong TYK2 catalytic inhibition, some JAK2 catalytic inhibition is still required to achieve complete inhibition of IL-23–induced phospho- STAT3. Similar to what was observed for IL-12 signaling, there was a correlation between phospho-STAT3 and IL-17F readouts downstream of IL-23 signaling (R2 = 0.64).
Our results indicate that IL-23–induced phosphorylation of STAT3 and IL- 17F production is regulated by TYK2 catalytic activity, consistent with previous studies of TYK2-deficient mice and a TYK2- deficient human patient. However, in contrast with the IL-12 pathway readouts, JAK2 catalytic activity may also contribute to the IL-23 pathway readouts.
https://www.jimmunol.org/content/jimmunol/191/5/2205.full.pdf?with-ds=yes
A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors
Our studies of the role of TYK2 catalytic activity in various human cytokine signaling pathways are consistent with studies of TYK2-deficient mice, but differ from the roles for TYK2 deduced from studies of a single TYK2-deficient human patient. TYK2 deficiency results in pathway-specific impairment of immune responses in mice, characterized by a reduced ability of IFN-a to induce type I IFN-responsive genes and antiviral responses, an inability of IL-12 to induce IFN-g production from T cells and NK cells and an inability of IL-23 to induce IL-17 production from T cells.
However, the IL-10 responses of T cells and myeloid cells and the IL-6 responses of T cells remain intact in TYK2-deficient mice.
IFN-a, IL-6, IL-10, and IL-22
In humans, TYK2 deficiency has also been associated with the abrogation of IL-12 and IL-23 responses in a single patient who exhibited hyper-IgE syndrome.
However, this patient was also shown to have additional defects in type I IFN, IL-6, and IL-10 signaling, suggesting that TYK2 deficiency may affect a broader group of cytokines in humans than in mice.
Together with a lack of significant inhibitory activity of the TYK2-selective compounds in the primary cell assays and the superposition of the inhibitory curves for combined treatment with JAK1 and TYK2 selective compounds together versus treatment with the JAK1-selective compound alone, these results indicate that JAK1 kinase activity and not TYK2 kinase activity is important for these signaling events.
However, in our IFN-a, IL-6, IL-10, and IL-22 assays, we sometimes observe a partial inhibition of readouts by our TYK2-selective compounds, resulting in up to 50% inhibition of assay readouts at the highest compound concentrations. These effects occur at concentrations of the TYK2-selective compounds that are much higher than their cellular potencies against TYK2 in the TYK2 reference cell assay. This inhibition of assay readouts at very high concentrations of the TYK2-selective compounds may thus be caused by partial inhibition of JAK1 kinase activity and/or off-target effects of the compounds at these concentrations.
Results
Effects of TYK2 versus JAK2 inhibition on IL-12 and IL-23 signaling
We observed in the IL-12 assays, where there was a good correlation with TYK2 catalytic inhibition but poor correlation with JAK2 catalytic inhibition. This suggests that these aspects of IL-23 signaling may depend on both TYK2 and JAK2 catalytic activity. The contribution of JAK2 catalytic activity to IL-23–induced phospho-STAT3 and IL-17F is particularly apparent for those compounds with the highest degree of TYK2 selectivity over JAK2.