Thursday, December 3, 2015

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(,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 JAK2WT and JAK2V617F 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 (Km) [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 (JAK2V617F 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 (FLT3D835Y enzyme assay) = 6 nM

1H NMR (Estimated) for Pacritinib

1. Hart, S.; et. al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 201125(11), 1751-1759.