Drugs in Clinical Pipeline: AZD1480

AZD1480 [(S)-5-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine] is an oral, potent, ATP competitive, small molecule inhibitor of Janus Kinase 2 (JAK2) kinase, with an inhibition constant (K_i) of 0.26 nM. 

To evaluate Jak family selectivity of AZD1480, enzymatic assays were carried out Jak1, Jak2, and Jak3  at K_m levels of ATP and 5 mM ATP, which is the high end of ATP concentrations in cells. AZD1480 demonstrated significant Jak2 selectivity over Jak3, in particular at high ATP concentrations and marginal selectivity over Jak1 at K_m ATP [1].

The activity of AZD1480 is as follows:

IC₅₀ (JAK1 enzyme assay, K_m ATP) = 1.3 ± 0.1 nM

IC₅₀ (JAK2 enzyme assay, K_m ATP) = less than 0.4 nM

IC₅₀ (JAK3 enzyme assay, K_m ATP) = 3.9 ± 0.7 nM

IC₅₀ (JAK1 enzyme assay, 5 mM ATP) = 41 ± 1.0 nM

IC₅₀ (JAK2 enzyme assay, 5 mM ATP) = 58 ± 2.4 nM

IC₅₀ (JAK3 enzyme assay, 5 mM ATP) = 1363 ± 113 nM

References:

1. Zinda, M.; et. al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009, 16(6), 487-497.