Pacritinib (SB1518) 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).

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. 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).

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

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 (~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. 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 ~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 ~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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

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 (~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. 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 ~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 ~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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

• . Hart S, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia. 2011 Nov;25(11):1751-9.  [Content Brief]

  . Hart S, et al. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J. 2011 Nov;1(11):e44.  [Content Brief]

  . William AD, et al. Discovery of the macrocycle 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 (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JA  [Content Brief]