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Pacritinib (SB1518)

JAK2/FLT3 inhibitor CAS# 937272-79-2

Pacritinib (SB1518)

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Chemical structure

Pacritinib (SB1518)

3D structure

Chemical Properties of Pacritinib (SB1518)

Cas No. 937272-79-2 SDF Download SDF
PubChem ID 46216796 Appearance Powder
Formula C28H32N4O3 M.Wt 472.58
Type of Compound N/A Storage Desiccate at -20°C
Synonyms SB1518
Solubility DMSO : 5.4 mg/mL (11.43 mM; Need ultrasonic and warming)
SMILES C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC=CC(=C4)C5=NC(=NC=C5)NC(=C3)C=C2
Standard InChIKey HWXVIOGONBBTBY-ONEGZZNKSA-N
Standard InChI 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+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Pacritinib (SB1518)

DescriptionPacritinib is a potent inhibitor of both wild-type JAK2 (IC50=23 nM) and JAK2V617F mutant (IC50=19 nM). Pacritinib also inhibits FLT3 (IC50=22 nM) and its mutant FLT3D835Y (IC50=6 nM).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[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-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[1]. 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[3].

References:
[1]. 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. [2]. 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. [3]. 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

Protocol

Kinase Assay [1]
All assays are carried out in 384-well white microtiter plates. Compounds (e.g., Pacritinib) are 4-fold serially diluted in 8 steps, starting from 10 µM. The reaction mixture consist 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 contain 2.0 µg/mL FLT3 enzyme, 5 µM of poly(Glu,Tyr) substrate and 4 µM of ATP. For JAK1 assays, the reaction contain 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 contain 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 contain 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 contain 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 detection reagent. After 10 min incubation luminescent signals are read on a multi-label plate reader[1].

Cell Assay [1]
SET-2 and Karpas 1106P cells, and Ba/F3-JAK2V617F-GFP-Luc cells are used. For proliferation assays in 96-well plates, cells are seeded at 30-50% confluency and are treated the following day with compounds (e.g., Pacritinib) (in triplicate) at concentrations up to 10 μM for 48 h. Cell viability is monitored using the CellTiter-Glo assay. Dose-response curves are plotted to determine IC50 values for the compounds using the XL-fit software[1].

Animal Administration [1][3]
Mice[1] Female athymic BALB/c nude mice (BALB/cOlaHsd-Foxn1nu) of age 12 weeks are used; and female SCID Beige mice (CB17.Cg-PrkdcscidLystbg/Crl) of age 9-10 weeks are used. For the SET-2 leukemia model, 5×106 tumor cells are injected subcutaneously in the right flank of severe combined immunodeficient beige mice. The cells are resuspended in 50 μL serum-free growth medium, mixed 1:1 with Matrigel and injected in a total volume of 100 μL. Tumor volumes are determined by caliper measurements and drug treatment is initiated after 31 days when tumors have reached a mean volume of 280 mm3 (tumor volume (mm3)=(w2×l)/2). This study is performed using 12 mice per group and animals are killed 3 h post-dose on day 18. Tumor growth inhibition is calculated. For the efficacy studies, mice are treated by oral gavage (10 mL/kg body weight) with doses from 50 to 150 mg/kg SB1518. Rats and Dogs[3] Male Wistar rats (aged 6-8 weeks, weighing 270 to 325 g) and male Beagle dogs (6 to 7 months of age, weighing 9-11 kg) are used in this study. The oral doses for dogs and rats are 3, and 10 mg/kg, respectively. The doses are administered, by gavage, as suspensions (0.5 % methylcellulose and 0.1%tween 80) to rats, and as gelatin capsules to dogs. Following oral dosing, serial blood samples are collected (jugular vein in dogs, and superior vena cava in rats) at different time points (0 to 24 h) in tubes containing K3EDTA as anticoagulant, and centrifuged, the plasma is separated and stored at -70°C until analysis. Plasma samples are processed and analyzed by LC/MS/MS. Pharmacokinetic parameters are estimated by noncompartmental methods using WinNonlin.

References:
[1]. 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. [2]. 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. [3]. 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

Pacritinib (SB1518) Dilution Calculator

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Preparing Stock Solutions of Pacritinib (SB1518)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.116 mL 10.5802 mL 21.1604 mL 42.3209 mL 52.9011 mL
5 mM 0.4232 mL 2.116 mL 4.2321 mL 8.4642 mL 10.5802 mL
10 mM 0.2116 mL 1.058 mL 2.116 mL 4.2321 mL 5.2901 mL
50 mM 0.0423 mL 0.2116 mL 0.4232 mL 0.8464 mL 1.058 mL
100 mM 0.0212 mL 0.1058 mL 0.2116 mL 0.4232 mL 0.529 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Pacritinib (SB1518)

Pacritinib is a small molecule inhibitor of Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) with IC50 values of 23nM, 19nM and 22nM, respectively for JAK2WT, JAK2V617F and FLT3 [1].

Pacritinib inhibits the JAK2-mediated production of p-STAT5 and p-STAT3 in Ba/F3 cells and the production of p-FLT3 and p-STAT5 in MV4-11 cells. It is less active against CYP3A4 and has good selectivity and microsomal stability. Pacritinib is proved to be high permeable in a Caco-2 bidirectional permeability assay. Additionally, pacritinib has a good oral bioavailability. In the Ba/F3-JAK2V617F mouse allograft, 150mg/kg treatment of pacritinib significantly alleviates the disease symptoms. In the MV4-11 xenografts, 50mg/kg and 100 mg/kg pacritinib treatments both show a significantly increased median survival of 55 days [1].

References:
[1] William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. 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 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011 Jul 14;54(13):4638-58.

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References on Pacritinib (SB1518)

Metabolism and Disposition of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans.[Pubmed:25600203]

Drug Metab Lett. 2015;9(1):28-47.

The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was >10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled mass balance and QWBA studies in mice, ~91% of the dose was recovered in feces, suggesting biliary clearance, and maximum radioactivity was seen in the gastrointestinal tract followed by the kidney, heart and low activity in the brain. The relatively high exposures of Pacritinib in humans might be attributed to its very high plasma protein binding, low metabolic and/or biliary clearance.

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia.[Pubmed:22829080]

Blood Cancer J. 2011 Nov;1(11):e44.

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC(50)=22 n) and Janus kinase 2 (JAK2, IC(50)=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis.[Pubmed:25762180]

Blood. 2015 Apr 23;125(17):2649-55.

Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000x 10(9)/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a >/=35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a >/=50% reduction in spleen size by physical examination. Median MF symptom improvement was >/=50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550.

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML.[Pubmed:22829971]

Blood Cancer J. 2012 May;2(5):e69.

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.

Description

Pacritinib is a potent inhibitor of both wild-type JAK2 (IC50=23 nM) and JAK2V617F mutant (IC50=19 nM). Pacritinib also inhibits FLT3 (IC50=22 nM) and its mutant FLT3D835Y (IC50=6 nM).

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