The JAK2-STAT signaling pathway is responsible for the proliferation of new blood cells. Hyperactive signaling caused by the V617F mutation in the JAK2 pseudokinase (JH2) domain is the cause of many myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis. Current drugs on the market that treat these disorders target the kinase (JH1) domain and tend to overcorrect for this hyperactive blood cell proliferation, leading to anemia and reduced levels of lymphocytes and platelets. While the natural substrate for the JH1 domain is ATP, the JH2 domain is also capable of binding ATP, but lacks the catalytic activity of the JH1 domain. Mutations around the ATP binding pocket of the mutant V617F JH2 domain have been shown to attenuate hyperactive signaling, implicating the JH2 domain with a regulatory role. This suggests that the hyperactive V617F JAK2 may be controlled with a small molecule that displaces ATP bound to the JH2 domain. We have previously reported several ligand series aimed at selectively targeting the JAK2 JH2 domain over the JH1 domain. Using SAR lessons derived from our triazole and triazine series, we opted to implement this knowledge in service of recovering a smaller false positive from virtual screening. Modest structural changes to our false positive converted it into a new lead molecule, and further derivatization yielded JAK2 JH2 ligands with improved binding affinity and selectivity over the JH1 domain compared to previously reported analogues.

Evolution of a false positive into potent ligands that selectively target the JAK2 pseudokinase domain for treating myeloproliferative neoplasms

ACS Spring 2022

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