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Pacritinib(SB1518)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Pacritinib(SB1518)图片
CAS NO:937272-79-2
规格:≥98%
包装与价格:
包装价格(元)
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)472.58
FormulaC28H32N4O3
CAS No.937272-79-2
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 11 mg/mL (23.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Other infoChemical Name: 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
InChi Key: HWXVIOGONBBTBY-ONEGZZNKSA-N
InChi Code: InChI=1S/C28H32N4O3/c1-2-13-32(12-1)14-17-35-27-9-8-25-19-24(27)21-34-16-4-3-15-33-20-22-6-5-7-23(18-22)26-10-11-29-28(30-25)31-26/h3-11,18-19H,1-2,12-17,20-21H2,(H,29,30,31)/b4-3+
SMILES Code: C1(C2=NC(NC3=CC=C(OCCN4CCCC4)C(COC/C=C/COC5)=C3)=NC=C2)=CC5=CC=C1
SynonymsPacritinib; SB-1518; Vonjo; SB1518; SB 1518
实验参考方法
In Vitro

In vitro activity: Pacritinib (Vonjo) is a potent inhibitor of both wild-type JAK2 and JAK2V617F mutant (IC50= 19 nM) that is present in high frequencies among patients with MPD. Relative to JAK2, Pacritinib 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). Pacritinib effectively permeates cells to modulate signaling pathways downstream of JAK2, whether agonist activated or mutationally activated. Pacritinib induces apoptosis, cell cycle arrest and antiproliferative effects in JAK2WT- and JAK2V617F-dependent cells. Pacritinib inhibits cell proliferation of Karpas 1106P and Ba/F3-JAK2V617F with IC50 of 348 and 160 nM, respectively. Pacritinib inhibits endogenous colony growth derived from erythroid and myeloid progenitors with IC50 of 63 and 53 nM , respectively. SB1518 also inhibits FLT3 and its mutant FLT3-D835Y(IC50= 6 nM ). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Pacritinib treatment leads to a dose-dependent decrease of pFLT3, pSTAT5, pERK1/2 and pAkt in FLT3-ITD harboring MV4-11 cells with IC50 of 80, 40, 33 and 29 nM , respectively. Treatment of the primary AML blast cells with Pacritinib for 3 h leads to a dose-dependent decrease of pFLT3, pSTAT3 and pSTAT5 with an IC50 below 0.5 μM. Pacritinib induces apoptosis, cell cycle arrest and anti-proliferative effects in FLT3-mutant and FLT3-wt cells. Pacritinib inhibits cell proliferation of FLT3-ITD-harboring cells MV4-11 and primary AML blast cells with IC50s of 47 nM and 0.19-1.3 μM, respectively.


Kinase Assay: All assays are carried out in 384-well white microtiter plates. Compounds are 4-fold serially diluted in 8 steps, starting from 10 μM. The reaction mixture consisted of 25 μL assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 5 mM MnCl2, 1 mM DTT, 0.1 mM Na3VO4, 5 mM β-glycerol phosphate). For FLT3 assays, the reaction contains 2.0 μg/mL FLT3 enzyme, 5 μM of poly(Glu,Tyr) substrate and 4 μM of ATP. For JAK1 assays, the reaction contains 2.5 μg/mL of JAK1 enzyme, 10 μM of poly(Glu,Ala,Tyr) substrate and 1.0 μM of ATP. For JAK2 assays, the reaction contained 0.35 μg/mL of JAK2 enzyme, 10 μM of poly (Glu,Ala,Tyr) substrate and 0.15 μM of ATP. For JAK3 assays, the reaction contained 3.5 μg/mL of JAK3 enzyme, 10 μM of poly (Glu,Ala,Tyr) substrate and 6.0 μM of ATP. For TYK2 assays, the reaction contained 2.5 μg/mL of TYK2 enzyme, 10 μM of poly (Glu,Ala,Tyr) substrate and 0.15 μM of ATP. The reaction is incubated at room temperature for 2 h prior to addition of 13 μL PKLight(R) detection reagent. After 10 min incubation luminescent signals are read on a multi-label plate reader.


Cell Assay: Cells (Karpas 1106P cells) are seeded at 30-50% confluency in 96-well plates and are treated with different concentrations of compounds (in triplicate) for 48 h. Cell viability is monitored using the CellTiter-Glo assay.

In VivoPacritinib administrated at 150 mg/kg p.o. q.d. to JAK2V617F-dependent xenograft model, significantly ameliorates splenomegaly and hepatomegaly symptoms, with 60% normalization of spleen weight and 92% normalization of liver weight and is well tolerated without significant weight loss or any hematological toxicities, including thrombocytopenia and anemia. Pacritinib induces dose-dependent inhibition of tumor growth of JAK2V617F-dependent SET-2 xenograft model (40% for 75 mg/kg and 61% for 150 mg/kg). [1] Pacritinib is efficacious in FLT3-ITD-bearing MV4-11 xenograft models. Pacritinib treated once daily for 21 consecutive days, induces dose-dependent inhibition of tumor growth (38% for 25 mg/kg, 92% for 50 mg/kg and 121% for 100 mg/kg). Complete regression is observed in 3/10 and 8/8 mice for the 50 and 100 mg/kg/day groups, respectively.
Animal modelHuman megakaryoblastic leukemia xenografts SET-2
Formulation & DosageDissolved in 0.5% methylcellulose (w/v) and 0.1% Tween-80 in H2O; 150 mg/kg; oral gavage
References

Leukemia. 2011 Nov;25(11):1751-9; Blood Cancer J. 2011 Nov;1(11):e44.

生物活性


Pacritinib effectively blocks FLT3 signaling in FLT3-ITD (MV4-11, MOLM-13) or FLT3-wt (RS;4-11) cells. Blood Cancer J. 2011 Nov;1(11):e44.



Pacritinib is efficacious in xenografts derived from cell lines harboring FLT3-ITD. Blood Cancer J. 2011 Nov;1(11):e44.


Activated JAK2 signaling in MV4-11 cells after selective inhibition of FLT3 induces FLT3-TKI resistance. Blood Cancer J. 2011 Nov;1(11):e44.


Pacritinib induces cell cycle arrest and apoptosis in FLT3-ITD- (MV4-11, MOLM-13) and FLT3-wt- (RS;4-11) harboring cancer cells. Blood Cancer J. 2011 Nov;1(11):e44.


Pacritinib inhibits proliferation of AML cells with highest potency in FLT3-ITD harboring cells. Blood Cancer J. 2011 Nov;1(11):e44.


Pacritinib blocks proliferation and induces apoptosis in ex vivo expanded primary AML blast cells. Blood Cancer J. 2011 Nov;1(11):e44.