Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms

Herein,
we describe the design, synthesis, and structure–activity
relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine
derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3
kinases. These screening cascades revealed that 18e was
a preferred compound, with IC50 values of 0.7 and 4 nM
for JAK2 and FLT3, respectively. Moreover, 18e was a
potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1
and JAK3, respectively, and possessed an excellent selectivity profile
over the other 100 representative kinases. In a series of cytokine-stimulated
cell-based assays, 18e exhibited a higher JAK2 selectivity
over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor
growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft
models, respectively. Additionally, 18e showed an excellent
bioavailability (F = 58%), a suitable half-life time
(T1/2 = 4.1 h), a satisfactory metabolic
stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative
neoplasms and FLT3-internal tandem duplication-driven acute myelogenous
leukemia.