Pacritinib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Pacritinib (SB1518) 是 Janus Kinase 2 (JAK2) 和 Fms-Like Tyrosine Kinase-3 (FLT3) 的有效选择性抑制剂，在无细胞测定中 IC50 分别为 23 和 22 nM。

Pacritinib (SB1518) is a potent and selective inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with IC50s of 23 and 22 nM in cell-free assays, respectively. Phase 3.(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 (Km). 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-JAK2V617F 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). (In Vivo):For evaluation of efficacy in the Ba/F3-JAK2V617F 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 (tmax=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 (tmax=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.

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 (Km). 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-JAK2V617F 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).

For evaluation of efficacy in the Ba/F3-JAK2V617F 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 (tmax=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 (tmax=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.

SB1518

Angiogenesis

FLT

FLT3| FLT3 (D835Y)| JAK2| JAK2 (V617F)| Tyk2| JAK3

Other Indications

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937272-79-2

472.58

C28H32N4O3

>98% (HPLC)

DMSO:11 mg/mL warmed (23.27 mM); Ethanol:<1 mg/mL (<1 mM); Water:<1 mg/mL (<1 mM)

C1(C2=NC(NC3=CC=C(OCCN4CCCC4)C(COC/C=C/COC5)=C3)=NC=C2)=CC5=CC=C1

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

(-20℃)

With Ice Pack

≥ 2 years