JAK1 similar to JAK2 has broad activity and receives signals from a number of cytokine receptors including IL-2 family, IL-4 family, and gp130 receptor family among others. JAK1 signaling is involved in both cellular proliferation and cell survival. JAK3 is more restricted to immune cells differentiation and proliferation. Some JAK2 inhibitors also inhibit other kinases in the family of cytoplasmic protein-tyrosine kinases.
A mutation associated with JAK2, called V617F, was found in substantial proportion of patients with several distinct chronic myelofibrosis diseases, and results in increased JAK2 signaling.
In vitro, INCY's compound has demonstrated selective inhibition of JAK2 (<1nM) and JAK1 and >500-fold selectivity against a broad range of other kinases.
EXEL's compound is a potent inhibitor of JAK2 with an IC50 of 2nM and selectivity against other members of the JAK kinase family with IC50 of 130nM and 250nM for JAK1 and JAK3, respectively.
So, the EXEL's compound is a more selective JAK2 inhibitor, while INCY's also strongly inhibits JAK1. Is this an advantage? data are immature but my hunch is that SE (neurotox) with the XL019 will be worse but its efficacy in myelofibrosis patients present with high blast counts may give it some good points.
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