Pacritinib

Catalog No.S8057 Batch:S805701

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Technical Data

Formula

C28H32N4O3
Molecular Weight 472.58 CAS No. 937272-79-2
Solubility (25°C)* In vitro DMSO 11 mg/mL (23.27 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or 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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description Pacritinib 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.
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)		 View More
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]
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]
Features Dual JAK2/FLT3 inhibitor that has progressed to Phase III clinical trials for treatment of Myelofibrosis.

Protocol (from reference)

Kinase Assay:[1]
  • 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 Assay:[1]
  • 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.
Animal Study:[1]
  • Animal Models

    Human megakaryoblastic leukemia xenografts SET-2

  • Dosages

    150 mg/kg

  • Administration

    oral gavage

Customer Product Validation

Data from [Data independently produced by , , Clin Cancer Res, 2016, 22(24):6118-6128]

Selleck's Pacritinib has been cited by 18 publications

A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics [ Cell Rep Med, 2024, 5(10):101748] PubMed: 39332415
Pacritinib inhibits proliferation of primary effusion lymphoma cells and production of viral interleukin-6 induced cytokines [ Sci Rep, 2024, 14(1):4125] PubMed: 38374336
Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms [ Am J Hematol, 2023, 98(7):1029-1042] PubMed: 37203407
IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia [ J Gen Virol, 2023, 104(5)001858] PubMed: 37256770
TLR4 aggravates microglial pyroptosis by promoting DDX3X-mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury [ Clin Transl Med, 2022, 12(6):e894] PubMed: 35692100
IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation [ Front Immunol, 2022, 13:1001068] PubMed: 36131914
Comprehensive drug response profiling and pan-omic analysis identified therapeutic candidates and prognostic biomarkers for Asian cholangiocarcinoma [ iScience, 2022, 25(10):105182] PubMed: 36248745
Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway [ Int J Mol Sci, 2022, 23(14)7853] PubMed: 35887201
Pacritinib Inhibition of IRAK1 Blocks Aberrant TLR8 Signalling by SARS-CoV-2 and HIV-1-Derived RNA [ J Innate Immun, 2022, 1-11] PubMed: 35785771
Establishment and characterization of immortalized sweat gland myoepithelial cells [ Sci Rep, 2022, 12(1):7] PubMed: 34997030

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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