Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core

Janus
kinases (JAKs) are non-receptor tyrosine kinases that are
essential components of the JAK-STAT signaling pathway. Associated
aberrant signaling is responsible for many forms of cancer and disorders
of the immune system. The present focus is on the discovery of molecules
that may regulate the activity of JAK2 by selective binding to the
JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation
in JH2 stimulates the activity of the adjacent kinase domain (JH1)
resulting in myeloproliferative disorders. Starting from a non-selective
screening hit, we have achieved the goal of discovering molecules
that preferentially bind to the ATP binding site in JH2 instead of
JH1. We report the design and synthesis of the compounds and binding
results for the JH1, JH2, and JH2 V617F domains, as well as five crystal
structures for JH2 complexes. Testing with a selective and non-selective
JH2 binder on the autophosphorylation of wild-type and V617F JAK2
is also contrasted.