Wednesday, December 2, 2015

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 (Ki) of 0.26 nM. 

To evaluate Jak family selectivity of AZD1480, enzymatic assays were carried out Jak1, Jak2, and Jak3  at Km 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 Km ATP [1].

The activity of AZD1480 is as follows:

IC50 (JAK1 enzyme assay, Km ATP) = 1.3 ± 0.1 nM
IC50 (JAK2 enzyme assay, Km ATP) = less than 0.4 nM
IC50 (JAK3 enzyme assay, Km 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

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.