Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof

The discovery that aberrant activity
of Janus kinase 2 (JAK2) is
a driver of myeloproliferative neoplasms (MPNs) has led to significant
efforts to develop small molecule inhibitors for this patient population.
Ruxolitinib and fedratinib have been approved for use in MPN patients,
while baricitinib, an achiral analogue of ruxolitinib, has been approved
for rheumatoid arthritis. However, structural information on the interaction
of these therapeutics with JAK2 remains unknown. Here, we describe
a new methodology for the large-scale production of JAK2 from mammalian
cells, which enabled us to determine the first crystal structures
of JAK2 bound to these drugs and derivatives thereof. Along with biochemical
and cellular data, the results provide a comprehensive view of the
shape complementarity required for chiral and achiral inhibitors to
achieve highest activity, which may facilitate the development of
more effective JAK2 inhibitors as therapeutics.