Pacritinib

937272-79-2

C28H32N4O3

DMSO : 5.4 mg/mL (11.43 mM; Need ultrasonic and warming)

Protein Tyrosine Kinase/RTK; Epigenetics; Stem Cell/Wnt; JAK/STAT Signaling

Pacritinib is a potent inhibitor of both wild-type JAK2 (IC₅₀=23 nM) and JAK2^V617F mutant (IC₅₀=19 nM). Pacritinib also inhibits FLT3 (IC₅₀=22 nM) and its mutant FLT3^D835Y (IC₅₀=6 nM). IC50 & Target: IC50: 6 nM (FLT3^D835Y), 22 nM (FLT3^wt), 19 nM (JAK2^V617F), 23 nM (JAK2^wt)^[1] In Vitro: Relative to JAK2, Pacritinib (SB1518) is two-fold less potent against TYK2 (IC₅₀=50 nM), 23-fold less potent against JAK3 (IC₅₀=520 nM) and 56-fold less potent against JAK1 (IC₅₀=1280 nM). The rest of the evaluated kinases show <30% inhibition when tested against 100 nM Pacritinib at adenosine triphosphate concentrations equivalent to its Michaelis constant (K_m). Pacritinib inhibits MV4-11 and MOLM-13 cells (both of which are cell lines derived from human acute myeloid leukemias driven by an FLT3 ITD mutation) with IC₅₀ of 47 and 67 nM, respectively. Pacritinib inhibits Karpas 1106P and Ba/F3-JAK2^V617F cells (which are cell lines dependent on JAK2 signaling) with IC₅₀ of 348 and 160 nM, respectively^[1]. FLT3-ITD harboring MV4-11 cells are treated for 3 h with different concentrations of Pacritinib (SB1518) and pFLT3, pSTAT5 and pERK1/2 levels are quantified. Pacritinib leads to a dose-dependent decrease of pFLT3, pSTAT5, pERK1/2 and pAkt with IC₅₀ of 80, 40, 33 and 29 nM, respectively. The IC₅₀ on auto-phosphorylation of FLT3-wt in RS4; 11 is four-fold higher (IC₅₀=600 nM) compare with FLT3-ITD in MV4-11 and MOLM-13 cells. However, STAT5 inhibition is detected at much lower concentrations of Pacritinib (IC₅₀=8 nM)^[2]. In Vivo: For evaluation of efficacy in the Ba/F3-JAK2^V617F engraftment model, mice are treated with Pacritinib (SB1518) at doses of 50 or 150 mg/kg p.o. q.d. for 13 days, with drug dosing starting 4 days after cell inoculation. At study termination, the vehicle control mice exhibit splenomegaly and hepatomegaly (ca.7- and 1.3-fold, respectively), reminiscent of the symptoms found in patients with symptomatic myelofibrosis. SB1518 treatment at 150 mg/kg p.o. q.d. significantly ameliorates all these symptoms, with 60% (+/-9%) normalization of spleen weight and 92% (+/-5%) normalization of liver weight and is well tolerated without significant weight loss or any hematological toxicities, including thrombocytopenia and anemia^[1]. In rats, Pacritinib (SB1518) shows moderately fast absorption (t_max=4 h), with a peak concentration of 114 ng/mL, AUC of 599 ng-h/mL, and a terminal half-life of ca.6 h following a single oral dose of 10 mg/kg. In dogs, Pacritinib (SB1518) is rapidly absorbed (t_max=2.0 h), with a peak concentration of ca.12 ng/mL, AUC of 53 ng-h/mL, and a terminal half-life of 3.4 h following a single oral dose of 3 mg/kg^[3].