Rationale: VR588 is promising pan-JAK inhibitor suited to inhalation
delivery. These studies were designed to characterise the invitro
kinase inhibition profile of VR588 and to determine its selectivity
versus non-JAK kinases.
Methods: Kinase activity was assessed in a non-cell (Z’Lyte
Florescence assay) and in cell based assays using stimulation of human
whole blood (IL-2 stimulated INFc production and JAK1/JAK3
and pSTATa/b activation and IL-6 stimulated pSTAT3 to assess
JAK1, JAK2 and Tyk2 activity). Selectivity of VR588 (1 mM) against
a panel of 93 human kinases was also assessed.
Results: VR588 potently inhibited JAK 1, 2, 3 and Tyk2 kinases
(IC50 4.2, 0.7, 2.1 & 6 nM respectively) in the non-cell based assay and
showed poor inhibitory activity against non –JAK kinases FLT3,
PDGFB, JNK2 and Syk (IC50 247, 2350,4000, 8900 nM respectively).
JAK inhibition was confirmed in the cell based assays with inhibition of
IL-2 stimulated INFc, IL-2 stimulated pSTATa/b & IL-6 stimulated
pSTAT3 demonstrating IC50 values of 209, 29 & 62 nM respectively.
Selectivity versus human kinases revealed no relevant off- target effects.
Conclusions: VR588 represents a potent, selective and balanced
pan-JAK inhibitor, suggesting VR588 may have utility as a treatment
for asthma and COPD.