Discovery of Potent and
Selective Pyrazolopyrimidine
Janus Kinase 2 Inhibitors
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Abstract
The discovery of somatic Jak2 mutations in patients with
chronic
myeloproliferative neoplasms has led to significant interest in discovering
selective Jak2 inhibitors for use in treating these disorders. A high-throughput
screening effort identified the pyrazolo[1,5-<i>a</i>]pyrimidine
scaffold as a potent inhibitor of Jak2. Optimization of lead compounds <b>7a</b>–<b>b</b> and <b>8</b> in this chemical
series for activity against Jak2, selectivity against other Jak family
kinases, and good in vivo pharmacokinetic properties led to the discovery
of <b>7j</b>. In a SET2 xenograft model that is dependent on
Jak2 for growth, <b>7j</b> demonstrated a time-dependent knock-down
of pSTAT5, a downstream target of Jak2