Janus kinase 2 (JAK2), is an intracellular, non-receptor tyrosine kinase that plays an essential role in hematopoiesis through the JAK-STAT signaling pathway. Under physiological conditions, the ATP-binding pseudokinase domain (JH2) of JAK2 regulates the activity of the canonical kinase domain (JH1). The V617F mutation in the JAK2 JH2 domain results in aberrant hyperactivation of the JH1 domain, and was deemed as the underlying cause of various myeloproliferative disorders (MPDs), including polycythemia vera, myelofibrosis, and essential thrombocythemia. Drug discovery efforts for MPDs have been mainly focused on targeting the JAK2 JH1 domain, yielding agents that are non-selective, multi-kinase binders. As a consequence, existing treatments for MPDs are beleaguered by undesirable side effects such as anemia and thrombocytopenia. An alternative strategy would be to reduce the hyperactivation of the pathogenic JAK2 JH2<sup>V617F </sup>through targeting the less conserved, non-catalytic JAK2 JH2 domain, with the potential to provide more selective therapies. To pursue this challenge, we initially aimed to discover small molecules that can selectively bind and block ATP binding to JAK2 JH2 in preference to the JH1 domain. Our medicinal chemistry endeavors were focused on leveraging structural differences of the two domains to elicit selectivity, utilizing a breadth of studies that comprised computational design, synthesis, <i>in vitro </i>assaying and crystallography. Starting from a non-selective JAK2 JH2 binder with a diaminotriazole core, the structural evolution of this series toward potent and selective JAK2 JH2 binders is presented herein.

Engineering diaminotriazole ligands into ATP-mimetics for selective targeting of the Janus kinase 2 (JAK2) pseudokinase domain (JH2)

ACS Spring Meeting 2021

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