Pacritinib (SB1518)

For research use only.

Catalog No.S8057

7 publications

Pacritinib (SB1518) Chemical Structure

CAS No. 937272-79-2

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.

Selleck's Pacritinib (SB1518) has been cited by 7 publications

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  • Phosphorylation of the CSF-1R targets indicated was examined by immunoblotting

    Clin Cancer Res, 2016, 22(24):6118-6128. Pacritinib (SB1518) purchased from Selleck.

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Biological Activity

Description 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.
Features Dual JAK2/FLT3 inhibitor that has progressed to Phase III clinical trials for treatment of Myelofibrosis.
Targets
FLT3 (D835Y) [1]
(Cell-free assay)
JAK2 (V617F) [1]
(Cell-free assay)
FLT3 [1]
(Cell-free assay)
JAK2 [1]
(Cell-free assay)
TYK2 [1]
(Cell-free assay)
6 nM 19 nM 22 nM 23 nM 50 nM
In vitro

Pacritinib 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. [1] 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. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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HL60 NV\rN44xSW62aYDyc4xq\mW{YYTpeoUh[XO|YYm= M3vBdWFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iSFy2NEBk\WyuczygTWM2OCB;IEGuO|gh|ryPLh?= MnT3QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjh7NUOzPFYoRjJ6OUWzN|g3RC:jPh?=
AC10 M2THO2N6fG:2b4jpZ4l1gSCjc4PhfS=> MkDCNlQhcHK| M{\tRmN6fG:2b4jpZ4l1gSCjZ3HpcpN1KGi3bXHuJGFEOTBiY3XscJMh[XO|ZYPz[YQh[XNiY3XscEB3cWGkaXzpeJkh[W[2ZYKgNlQhcHK|IHL5JGNmdGyWaYTldk1IdG9iYYPzZZktKEmFNUCgQUAzNjB{IN88UU4> M2q4VlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ6OUWzN|g3Lz5{OEm1N|M5PjxxYU6=
TAMH MVvDfZRwfG:6aXPpeJkh[XO|YYm= NX3xPGM5OjRiaILz MoG1R5l1d3SxeHnjbZR6KGGpYXnud5QhXEGPSDDj[YxteyCjc4Pld5Nm\CCjczDj[YxtKH[rYXLpcIl1gSCjZoTldkAzPCCqcoOgZpkhS2WubGTpeIVzNUeubzDhd5NigSxiSVO1NEA:KDNwNkig{txONg>? NYnmZ3pYRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMki5OVM{QDZpPkK4PVU{Ozh4PD;hQi=>
KMS-12-BM NIf1cmlHfW6ldHnvckBie3OjeR?= MXqyJJVO NVfUSGJnOyCqcoO= NHHCWopKdmirYnn0bY9vKG:oIFrBT|IhcW5iSVytOk1{fGmvdXzheIVlKGi3bXHuJGtOWy1zMj3CUUBk\WyuczDhd5Nme3OnZDDhd{B{fXCycnXzd4lwdiCxZjDTWGFVOyCyaH;zdIhwenmuYYTpc44h[XRiVGm3NFUhemW|aXT1[UBifCB{IIXNJJBz\XS{ZXH0[YQh\m:{IEOgbJJ{KG[xbHzve4VlKGK7IFnMMVYhe3SrbYXsZZRqd25iYomgbY1ufW6xYnzveEBu\XSqb3S= NGnDRpc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{N{W0NVM2Pyd-Mke1OFE{PTd:L3G+
MOLM14 NGLWWpBHfW6ldHnvckBie3OjeR?= Mkj1NE4yKHWP M{LUdVMhcHK| NHLNfJpKdmirYnn0bY9vKG:oIFrBT|IhcW5iSVytOk1{fGmvdXzheIVlKGi3bXHuJG1QVE1zNDDj[YxteyCjc4Pld5Nm\CCjczDzeZBxemW|c3nvckBw\iCVVFHUN{BxcG:|cHjvdplt[XSrb36gZZQhXFl5MEWgdoV{cWS3ZTDheEAxNjFidV2gdJJmfHKnYYTl[EBnd3JiMzDodpMh\m:ubH;3[YQh[nliSVytOkB{fGmvdXzheIlwdiCkeTDpcY12dm:kbH;0JI1mfGixZB?= M3r2PVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ5NUSxN|U4Lz5{N{W0NVM2PzxxYU6=
HEL 92.1.7 MWfGeY5kfGmxbjDhd5NigQ>? MYSxJIhz NXe0NZRKUW6mdXP0bY9vKG:oIFrBT|IhXjZzN1[gcZV1[W62IIDoc5NxcG:{eXzheIlwdiCjdDDZNVAxPy96IILld4llfWW|IHnuJGhGVCB7Mj6xMlch[2WubIOgZYZ1\XJiMTDodkBjgSCrbX31co9jdG:2IH3leIhw\A>? M{S1UVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ5NUSxN|U4Lz5{N{W0NVM2PzxxYU6=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
pFLT3 / FLT3 / pSTAT5 / STAT5 / GAPDH; 

PubMed: 31102119     


In vitro activity of pacritinib in various FLT3-ITD+ models. (D) Signaling inhibition with pacritinib in Ba/F3 cells expressing different FLT3 double mutants via Western blot (representative images from two experiments).

p-STAT3Y705 / STAT3 / ACTIN / PARP; 

PubMed: 29253028     


Pacritinib effectively decreases BTIC viability and sphere forming capacity and has on-target activity on phospho-STAT3. (D) Pacritinib had on-target activity as seen by a decrease in the phosphorylation of tyrosine 705 at 3 hours. It also resulted in increased cell death as seen by an increase in the cleaved PARP at 24 hours (representative line BT69 shown).

pSTAT3 Y705 / STAT3 / β-Tubulin; 

PubMed: 29253028     


Pacritinib does not attenuate BTIC sensitivity to TMZ. (E) 1 μM pacritinib dramatically reduced phosphorylation of tyrosine 705 of STAT3 (p-STAT3 Y705) in BT53 at 48 hours. Treatment with 10 μg/mL TMZ resulted in a dramatic increase in p-STAT3 Y705. Combinatorial treatment with pacritinib and TMZ resulted in the abrogation of activated STAT3.

pSTAT3 Y705 / STAT3 / Actin / MAPK / p-AKT S473 / AKT; 

PubMed: 29253028     


Pacritinib inhibits STAT3 with minimal effects on other signaling pathways. Low micromolar concentrations of pacritinib reduced phosphorylation of tyrosine 705 of STAT3 in BT147 and BT53 at 3 hours, but did not affect phosphorylation of p44/42 MAPK or AKT S473. Pacritinib reduced phosphorylation of AKT S473 and p44/42 MAPK at higher concentrations (5 μM and 10 μM).

pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin; 

PubMed: 22829080     


Pacritinib effectively blocks FLT3 signaling in FLT3-ITD (MV4-11, MOLM-13) or FLT3-wt (RS;4-11) cells. (a) MV4-11 cells were treated with pacritinib, JAKi-1 and sunitinib for 3 h as indicated. After lysis, phosphorylation status of FLT3, STAT5, ERK1/2 and Akt were detected by immunoblotting (IB). As a loading control, the same membranes were re-probed with anti-actin antibody.

pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin; 

PubMed: 22829080     


Pacritinib effectively blocks FLT3 signaling in FLT3-ITD (MV4-11, MOLM-13) or FLT3-wt (RS;4-11) cells. As a loading control, the same membranes were re-probed with anti-actin antibody. (b) MOLM-13 and (c) RS4;11 cells were pre-treated with pacritinib for 3 h and stimulated for 3 min with 10 ng/ml FLT3 ligand as indicated. After lysis, the phosphorylation status of FLT3 and total actin were detected by IB.

31102119 29253028 22829080
Growth inhibition assay
Cell viability; 

PubMed: 29235481     


Effects of UC-514321 in treating AMLs. b–e Effects of NSC-370284, UC-514321, and other JAK/STAT pathway inhibitors, i.e., Pacritinib, KW-2449, Stattic and sc-355979, on the viability of AML cell lines MONOMAC-6 (b), THP-1 (c), KASUMI1 (d), and NB4 (e). Cells were treated with drugs at indicated doses. Cell viability was detected by MTS 48 h post treatment. Error bar indicates SD of triplicate experiments.

29235481
IHC
HE staining of liver sections; 

PubMed: 29785143     


Representative micrography of H&E-stained liver sections on day of death. H&E (hematoxylin and eosin).

HE staining of skin grafts; 

PubMed: 29382747     


(C) Histologic representations of the skin grafts uniformly harvested on day +21 demonstrate that pacritinib reduces lymphocytic infiltration (^) and severe basal vacuolar changes of the graft, such as the subepidermal blister (#). Low power at 6×, high-power Inset at 20×. (Scale bar, 400 µm.)

p-STAT3 / Ki-67 / mCD31 / VEGF-A / Bcl-2; 

PubMed: 32929154     


Combined treatment with JAK2 and SMO inhibitors synergize to reduce angiogenesis, tumor cell proliferation, and tumoral STAT3 activation of TNBC in vivo. (B) Representative IHC images of Bcl-2, VEGF-A, mCD31, Ki-67, and p-STAT3 (Y705) of treated MDA-231 MFP xenografts. Images were taken under 20X magnification. Arrows point to examples of positive staining.

29785143 29382747 32929154
Immunofluorescence
Phalloidin; 

PubMed: 27334834     


Pacritinib inhibits nurse-like cell viability. (C) NLC were generated from CLL patient PBMC and treated with ruxolitinib (5 μM), fedratinib (5 μM), pacritinib (1 μM) or vehicle control (DMSO). NLC were visualized by fluorescent microscopy 24 hours later after phalloidin and DAPI staining.

TUNEL; 

PubMed: 32929154     


(H) Representative images of TUNEL-positive staining of mammary fat pad xenografts from each treatment group. TUNEL, DAPI, and TUNEL-DAPI merged. Images were taken under 10X magnification. For all analyses, at least 5 fields were quantified per tumor section (N=4–5 tumors/group).

27334834 32929154
In vivo Pacritinib 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. [2]

Protocol

Kinase Assay:[1]
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kinase activity assays:

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® detection reagent. After 10 min incubation luminescent signals are read on a multi-label plate reader.
Cell Research:[1]
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  • Cell lines: Karpas 1106P cells
  • Concentrations: ~10 μM
  • Incubation Time: 2 days
  • Method: 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.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Human megakaryoblastic leukemia xenografts SET-2
  • Dosages: 150 mg/kg
  • Administration: oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 11 mg/mL warmed (23.27 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 472.58
Formula

C28H32N4O3

CAS No. 937272-79-2
Storage powder
in solvent
Synonyms N/A
Smiles C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
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Step 2: Enter the in vivo formulation ()
% DMSO % % Tween 80 % ddH2O
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Bio Calculators

Molarity Calculator

Molarity Calculator

Calculate the mass, volume or concentration required for a solution. The Selleck molarity calculator is based on the following equation:

Mass (mg) = Concentration (mM) × Volume (mL) × Molecular Weight (g/mol)

  • Mass
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*When preparing stock solutions, please always use the batch-specific molecular weight of the product found on the via label and SDS / COA (available on product pages).

Dilution Calculator

Dilution Calculator

Calculate the dilution required to prepare a stock solution. The Selleck dilution calculator is based on the following equation:

Concentration (start) x Volume (start) = Concentration (final) x Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2 ( Input Output )

  • C1
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    C2
    V2

* When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / COA (available online).

The Serial Dilution Calculator Equation

  • Serial Dilutions

  • Computed Result

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
Molecular Weight Calculator

Molecular Weight Calculator

Enter the chemical formula of a compound to calculate its molar mass and elemental composition:

Total Molecular Weight: g/mol

Tip: Chemical formula is case sensitive. C10H16N2O2 c10h16n2o2

Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter its chemical formula and click 'Calculate'.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04520269 Recruiting Drug: Pacritinib Breast Cancer National University Hospital Singapore July 13 2020 Phase 1|Phase 2
NCT03165734 Recruiting Drug: Pacritinib|Drug: Physician''s Choice medications Primary Myelofibrosis|Post-polycythemia Vera Myelofibrosis|Post-essential Thrombocythemia Myelofibrosis CTI BioPharma|PSI CRO June 26 2017 Phase 3
NCT02677948 Withdrawn Drug: Pacritinib|Drug: Ibrutinib Chronic Lymphocytic Leukemia|Lymphoma Small Lymphocytic University of Michigan Rogel Cancer Center October 2016 Phase 1|Phase 2
NCT02584777 Withdrawn Biological: Pacritinib Primary Myelofibrosis Baxalta now part of Shire|CTI BioPharma|Takeda November 30 2015 Phase 2
NCT02765724 Completed Drug: Pacritinib Myelofibrosis CTI BioPharma|SGS S.A. January 2015 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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JAK Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID