Elicit: Upadacitinib: JAK1/JAK3 Selectivity in Cytokine Signaling

Upadacitinib: JAK1/JAK3 Selectivity in Cytokine Signaling

Upadacitinib JAK1/JAK3 selectivity cytokine signaling

Reviewed literature on upadacitinib JAK selectivity.

Upadacitinib was engineered specifically to preserve JAK1 potency while sparing JAK3 — and the in-isolation data are clean, but at clinical RA doses the selectivity window is narrower than the biochemistry suggests.

In isolation (recombinant enzymes and engineered Ba/F3 lines): Upadacitinib inhibits JAK1 at 45 nM biochemically, with ~2.5-fold selectivity over JAK2, >40-fold over JAK3, and ~100-fold over TYK2; in engineered cells, JAK1 selectivity expands to ~40-fold over JAK2, ~130-fold over JAK3, and ~190-fold over TYK2 (Parmentier et al. 2018). The selectivity was designed in — a trifluoroethyl group exploits a "closed" glycine-rich loop conformation unique to JAK1 versus JAK2 (Parmentier et al. 2018). In physiologically relevant cells, IL-6/STAT3, OSM/STAT3, IL-2/STAT5, and IFNγ/STAT1 (all JAK1-dependent) are inhibited at low nM, while EPO/STAT5 (pure JAK2) requires ~60-fold higher concentrations (Parmentier et al. 2018).

JAK1 vs JAK3 in human blood: The cleanest readout is ex vivo from Phase 1 — IL-6-induced pSTAT3 (JAK1) and IL-7-induced pSTAT5 (JAK1/JAK3). EC50s were 61 nM (JAK1) and 125 nM (JAK1/JAK3) for upadacitinib, versus 119 nM and 79 nM for tofacitinib. The potency ratio is 2.0 for upadacitinib versus 0.67 for tofacitinib — about 3-fold greater JAK1-over-JAK3 selectivity for upadacitinib (Mohamed et al. 2019). But that ratio degrades with dose: doses ≥12 mg BID begin to lose JAK1 selectivity and produce NK-cell reductions consistent with JAK1/JAK3 engagement (Mohamed et al. 2019).

The clinically important nuance. At clinical RA exposures (15 mg QD), upadacitinib has the least relative JAK1 selectivity among the four approved JAKinibs — it inhibits JAK1/JAK3-dependent IL-4/pSTAT6, IL-2 and IL-15/pSTAT5, and JAK2-dependent G-CSF/pSTAT3 and GM-CSF/pSTAT5 more than filgotinib or baricitinib, with tofacitinib showing the highest JAK3 pathway coverage of the four (Través et al. 2021). In other words, the biochemical/cellular JAK1-over-JAK3 selectivity is real, but the dose required for full IL-6 pathway coverage in RA pushes exposures into a range where common γ-chain (JAK1/JAK3) signaling is still substantially inhibited.

So the short version: upadacitinib is a genuine JAK1-selective inhibitor (~10–100x over JAK3 depending on assay), about 3x more JAK1-vs-JAK3 selective than tofacitinib in humans, but its clinical dose sits at the edge of that selectivity window — which is the leading mechanistic hypothesis for the dose-dependent NK-cell, herpes zoster, and hematologic signals seen with the 30 mg arm versus 15 mg.