AI Article Synopsis
- Aberrant activity of JAK2 is linked to myeloproliferative neoplasms (MPNs), prompting the development of small molecule inhibitors like ruxolitinib and fedratinib.
- Structural details of how these inhibitors interact with JAK2 were previously unknown, which limited understanding of their effectiveness.
- The research introduces a method to produce JAK2 from mammalian cells, revealing crystal structures that clarify how both chiral and achiral inhibitors fit with JAK2, potentially aiding in the creation of more effective treatments.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327781 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.0c01952 | DOI Listing |
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