Drugs in Clinical Pipeline: Pacritinib | Dual Kinase Inhibitor | JAK2 Inhibitor | FLT3 Inhibitor

Pacritinib [11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene] is a novel low-molecular weight pyrimidine-based macrocycle with potent inhibitory activities against Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3). 

Pacritinib shows a unique kinase profile with selective inhibition of Janus Kinase-2 with IC₅₀ values of 23 and 19 nM against JAK2^WT and JAK2^V617F respectively and an IC₅₀ value of 22 nM gainst FLT3. Within the JAK family, Pacritinib has IC₅₀ values of 50, 520 and 1280 nM for TYK, JAK3 and JAK2, respectively, showing high preference for JAK2. The rest of the evaluated kinases showed less than 30% inhibition when tested against 100 nM Pacritinib at ATP concentrations equivalent to its Michaelis constant (K_m) [1].

Pacritinib: 2D and 3D Structure

The activity of Pacritinib is as follows:

IC₅₀ (JAK1 enzyme assay) = 1280 ± 370 nM
IC₅₀ (JAK2 enzyme assay) = 23 ± 6 nM
IC₅₀ (JAK2^V617F enzyme assay) = 19 nM
IC₅₀ (JAK3 enzyme assay) = 520 ± 110 nM
IC₅₀ (TYK2 enzyme assay) = 50 ± 6 nM
IC₅₀ (FLT3 enzyme assay) = 22 ± 6 nM
IC₅₀ (FLT3^D835Y enzyme assay) = 6 nM

1H NMR (Estimated) for Pacritinib

References:

1. Hart, S.; et. al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 2011, 25(11), 1751-1759.