Pacritinib (SB1518) is a potent inhibitor of both wild-typeJAK2(IC₅₀=23 nM) andJAK2^V617Fmutant (IC₅₀=19 nM). Pacritinib also inhibitsFLT3(IC₅₀=22 nM) and its mutantFLT3^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 IC₅₀of 47 and 67 nM, respectively. Pacritinib inhibits Karpas 1106P and Ba/F3-JAK2^V617Fcells (which are cell lines dependent on JAK2 signaling) with IC₅₀of 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 IC₅₀of 80, 40, 33 and 29 nM, respectively. The IC₅₀on 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].

For evaluation of efficacy in the Ba/F3-JAK2^V617Fengraftment 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^[1]. In rats, Pacritinib (SB1518) shows moderately fast absorption (t_max=4 h), with a peak concentration of 114 ng/mL, AUC of 599 ngoh/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 ngoh/mL, and a terminal half-life of 3.4 h following a single oral dose of 3 mg/kg^[3].

472.58

Solid

C₂₈H₃₂N₄O₃

937272-79-2

Room temperature in continental US; may vary elsewhere.

DMSO : 5 mg/mL(10.58 mM;Need ultrasonic)

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——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
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• 1.

  请依序添加每种溶剂： 10% DMSO    40%PEG300   5%Tween-80   45% saline

  Solubility: ≥ 1 mg/mL (2.12 mM); Clear solution

  此方案可获得 ≥ 1 mg/mL (2.12 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH2O 中，得到澄清透明的生理盐水溶液
• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20%SBE-β-CDin saline)

  Solubility: 1 mg/mL (2.12 mM); Suspended solution; Need ultrasonic

  此方案可获得 1 mg/mL (2.12 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。

  以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 5% DMSO    40%PEG300   5%Tween-80   50% saline

  Solubility: ≥ 0.3 mg/mL (0.63 mM); Clear solution