Selectivity over these other signaling molecules. At exposures that resulted in comparable efficacy to MRLB-11055, this inhibitor 1032350-13-2 demonstrated identical reductions in lymphocyte populations.Oneexplanation for these findings is that the reduction in these cell populations is due, at least in part, to inhibition of JAK2 itself, which is consistent with a role of JAK2-dependent cytokines such as IL-12 in lymphocyte development. We have demonstrated that intermittent GSK1016790A dosing can attenuate many of the undesirable effects that will likely be associated with the use of JAK2 inhibitors in the treatment of MPD. In addition to signaling downstream of the EPO receptor, JAK2 plays a role in mediating signaling from a variety of molecules, including IFNc, IL-6, TPO, GM-CSF, prolactin, growth hormone, and angiotensin 1. The JAK2 inhibitor TG101348 has been described as a molecule that is both efficacious in a murine model of PV and sparing of T lymphocytes. While inhibition of pSTAT5 was clearly demonstrated 2 hours after TG101348 administration, it is not clear how prolonged target inhibition was during dosing. As TG101348 required 42 days of continuous treatment to achieve hematocrit reductions of18,it is reasonable topresumethat targetengagement may have been lower relative to MRLB-11055 for a given dosing cycle. Thus the apparently unperturbed T lymphocyte populations maybe explained by a lower level of target engagement.Theeffect on NK cells, which responded most sensitively to MRLB-11055 inhibition, was not measured with TG101348. We have demonstrated that intermittent dosing of a JAK2 inhibitor can effectively normalize erythroid progenitor populations and thereby effectively treat conditions of polycythemia and splenomegaly in mouse models of PV. Our data can provide signficant guidance to the clinical development of JAK2 inhibitors. While the kinetics of erythropoesis are likely different in human disease, our data provide proof-of-concept for the use of erythroid progenitor populations as early biomarkers of target tissue efficacy, that could guide development of optimized intermittent dosing schemes to provide patients with improved therapy. Furthermore, our data show that lymphoid populations, in particular NK cells, serve as sensitive biomarkers for JAK inhibit
