A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies: the road not taken.

Jak2 is a non-receptor tyrosine kinase that is involved in the control of cellular growth and proliferation. Due to its significant role in hematopoiesis, Jak2 is a frequent target for mutations in cancer, especially myeloid leukemia, lymphoid leukemia and the myeloproliferative neoplasms (MPN). These mutations are common amongst different populations all over the world and there is a great deal of effort to develop therapeutic drugs for the affected patients. Jak2 mutations, whether they are point, deletion, or gene fusion, most commonly result in constitutive kinase activation. Here, we explore the structure-function relation of various Jak2 mutations identified in cancer and understand how they disrupt Jak2 regulation. Current Jak2 inhibitors target the highly conserved active site in the kinase domain and therefore, these inhibitors may lack specificity. Based on our knowledge regarding structure-function correlations as they pertain to regulation of Jak2 kinase activity, an alternative approach for specific Jak2 targeting could be via allosteric inhibitor design. Successful reports of allosteric inhibitors developed against other kinases provide precedent for the development of Jak2 allosteric inhibitors. Here, we suggest plausible target sites in the Jak2 structure for allosteric inhibition. Such targets include the type II inhibitor pocket and substrate binding site in the kinase domain, the kinase-pseudokinase domain interface, SH2-JH2 linker region and the FERM domain. Thus, future Jak2 inhibitors that target these sites via allosteric mechanisms may provide alternative therapeutic strategies to existing ATP competitive inhibitors.