Replies to post #77494 on Biotech Values

[poorgradstudent]

JAK1 and JAK2 do appear to mediate signaling by different receptors, but there is overlap. In other words, some work through one or the other, others work through both.

JAK2 signaling appears to be a bit more discrete over JAK1. The wikipedia articles give a nice quick overview if you're not inclined to dig super deep. Usually these types of mechanisms are very sensitive to cellular context.

As for EXEL's claims, I can't dispute them. But at this point, claiming importance for JAK2 specificity doesn't seem all that big a deal if you don't have clinical data to show that it matters. Know what I'm saying?

[genisi]

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.