1. Protein Tyrosine Kinase/RTK
    JAK/STAT Signaling
    Epigenetics
    Stem Cell/Wnt
  2. FLT3
    JAK

Pacritinib (Synonyms: SB1518)

Cat. No.: HY-16379 Purity: 99.66%
Data Sheet SDS Handling Instructions

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).

For research use only. We do not sell to patients.
Pacritinib Chemical Structure

Pacritinib Chemical Structure

CAS No. : 937272-79-2

Size Price Stock Quantity
5 mg $90 In-stock
10 mg $120 In-stock
50 mg $350 In-stock
100 mg $550 In-stock
200 mg   Get quote  
500 mg   Get quote  

* Please select Quantity before adding items.

Other Forms of Pacritinib:

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

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).

IC50 & Target

IC50: 6 nM (FLT3D835Y), 22 nM (FLT3wt), 19 nM (JAK2V617F), 23 nM (JAK2wt)[1]

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].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT02532010 Weill Medical College of Cornell University Acute Myeloid Leukemia (AML) June 2015 Phase 2
NCT02803762 CTI BioPharma|QPS-Qualitix Healthy July 2014 Phase 1
NCT02765724 CTI BioPharma|SGS S.A. Myelofibrosis January 2015 Phase 1
NCT02807116 CTI BioPharma|Covance Healthy Subjects January 2015 Phase 1
NCT02807051 CTI BioPharma|Covance Drug Interaction Study September 2014 Phase 1
NCT02277093 Washington University School of Medicine|CTI BioPharma Colorectal Cancer September 22, 2015 Phase 2
NCT03165734 CTI BioPharma|Covance Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis June 26, 2017 Phase 2
NCT02677948 University of Michigan Cancer Center Chronic Lymphocytic Leukemia|Lymphoma, Small Lymphocytic October 2016 Phase 1|Phase 2
NCT02564536 Washington University School of Medicine|CTI BioPharma Chronic Myelomonocytic Leukemia|Juvenile Myelomonocytic Leukemia|Atypical Chronic Myeloid Leukemia|Myeloproliferative Neoplasm|Myelodysplastic Syndromes|Myelofibrosis June 2017 Phase 1
NCT02469415 M.D. Anderson Cancer Center|CTI BioPharma Leukemia September 30, 2015 Phase 2
NCT02323607 Bhavana Bhatnagar|CTI BioPharma|Ohio State University Comprehensive Cancer Center Recurrent Adult Acute Myeloid Leukemia|Secondary Acute Myeloid Leukemia|Therapy-Related Acute Myeloid Leukemia|Untreated Adult Acute Myeloid Leukemia January 2016 Phase 1
NCT02342353 Washington University School of Medicine Non-Small Cell Lung Cancer|Nonsmall Cell Lung Cancer|Carcinoma, Non-Small-Cell Lung May 18, 2015 Phase 1|Phase 2
NCT02891603 H. Lee Moffitt Cancer Center and Research Institute|CTI BioPharma Graft Vs Host Disease|GVHD March 30, 2017 Phase 1|Phase 2
NCT02584777 Baxalta US Inc.|CTI BioPharma Primary Myelofibrosis November 2015 Phase 2
NCT01773187 CTI BioPharma Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis December 2012 Phase 3
NCT02808455 CTI BioPharma|Covance Healthy Subjects January 2015 Phase 1
NCT02055781 CTI BioPharma Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis December 2013 Phase 3
NCT02807077 CTI BioPharma|SGS S.A. Myelofibrosis November 2014 Phase 1
NCT02410551 M.D. Anderson Cancer Center|CTI BioPharma Myeloproliferative Diseases June 15, 2015 Phase 2
NCT02823171 CTI BioPharma|Covance Healthy August 2015 Phase 1
NCT02807207 CTI BioPharma|Covance Healthy Subjects October 2014 Phase 1
NCT02251821 Fred Hutchinson Cancer Research Center|National Cancer Institute (NCI)|National Heart, Lung, and Blood Institute (NHLBI) Primary Myelofibrosis|Secondary Myelofibrosis October 2014 Phase 2
NCT00719836 S*BIO Acute Myelogenous Leukemia|Chronic Myelogenous Leukemia|Chronic Myelomonocytic Leukemia|Myelodysplastic Syndromes|Myelofibrosis August 2008 Phase 1|Phase 2
NCT01263899 S*BIO Hodgkin Lymphoma|Mantle Cell Lymphoma|Indolent Lymphoma December 2010 Phase 2
NCT00745550 S*BIO Myelofibrosis|Myeloproliferative Disorders|Polycythemia Vera|Essential Thrombocythemia August 2008 Phase 1|Phase 2
NCT00741871 S*BIO Lymphoma, Malignant|Hodgkin's Lymphoma|B Cell Lymphoma July 2008 Phase 1
NCT01436084 M.D. Anderson Cancer Center|S*BIO Leukemia December 2011 Phase 2
View MoreCollapse
References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.1160 mL 10.5802 mL 21.1604 mL
5 mM 0.4232 mL 2.1160 mL 4.2321 mL
10 mM 0.2116 mL 1.0580 mL 2.1160 mL
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]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Pacritinib (SB1518) is dissolved in DMSO and stored, and then diluted with appropriate media before use[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]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1][3]

Pacritinib (SB1518) is prepared in 0.5%methylcellulose (w/v) and 0.1% Tween-80 in H2O (MC/Tween) (Mice)[1].
Pacritinib (SB1518) is suspended in 0.5 % methylcellulose and 0.1%tween 80 (Rat)[3].
Pacritinib (SB1518) is prepared as gelatin capsules to dogs (Dog)[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.
Rat and Dog[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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

472.58

Formula

C₂₈H₃₂N₄O₃

CAS No.

937272-79-2

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: < 4.7 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.66%

Inquiry Online

Your information is safe with us. * Required Fields.

Product name

 

Salutation

Applicant name *

 

Email address *

Phone number

 

Organization name *

Country *

 

Requested quantity *

Remarks

Bulk Inquiry

Inquiry Information

Product Name:
Pacritinib
Cat. No.:
HY-16379
Quantity: