Home JAK/STAT JAK inhibitor Pacritinib (SB1518)

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Pacritinib (SB1518) JAK2/FLT3 Inhibitor

Cat.No.S8057

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.
Pacritinib (SB1518) JAK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 472.58

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Quality Control

Batch: Purity: 99.94%
99.94

Products Often Used Together with Pacritinib (SB1518)

Pracinostat (SB939)

It and Pracinostat completely abrogate the JAK2-autophosphorylation and enhance cell death in Set-2 cells.

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MOLM14 Antiproliferative assay 48 hrs Antiproliferative activity against human MOLM14 cells harboring FLT3-ITD mutant after 48 hrs by CellTiter-Glo assay, IC50 = 0.079 μM. 27541357
MCF7 Antiproliferative assay 72 hrs Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay, IC50 = 0.29 μM. 27541357
HL60 Antiproliferative assay 48 hrs Antiproliferative activity against human HL60 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.52 μM. 27541357
KMS-12-BM Antiproliferative assay 48 hrs Antiproliferative activity against human KMS-12-BM cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.75 μM. 27541357
PC3 Antiproliferative assay 48 hrs Antiproliferative activity against human PC3 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.77 μM. 27541357
Jurkat Antiproliferative assay 48 hrs Antiproliferative activity against human Jurkat cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.839 μM. 27541357
MCF7 Antiproliferative assay 48 hrs Antiproliferative activity against human MCF7 cells after 48 hrs by CellTiter-Glo assay, IC50 = 0.85 μM. 27541357
HCT116 Antiproliferative assay 72 hrs Antiproliferative activity against human HCT116 cells after 72 hrs by MTT assay, IC50 = 0.88 μM. 27541357
Jurkat Antiproliferative assay Antiproliferative activity against human Jurkat cells, IC50 = 1.09 μM. 27541357
HEL 92.1.7 Antiproliferative assay 36 hrs Antiproliferative activity against HEL 92.1.7 cells harboring JAK2 V617F mutant after 36 hrs by PrestoBlue dye based assay, IC50 = 1.17 μM. 27541357
OPM2 Antiproliferative assay 48 hrs Antiproliferative activity against human OPM2 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.21 μM. 27541357
KHYG Antiproliferative assay 48 hrs Antiproliferative activity against human KHYG cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.24 μM. 27541357
KG1 Antiproliferative assay 48 hrs Antiproliferative activity against human KG1 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.48 μM. 27541357
NKYS Antiproliferative assay 48 hrs Antiproliferative activity against human NKYS cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.6 μM. 27541357
HCT116 Antiproliferative assay 48 hrs Antiproliferative activity against human HCT116 cells after 48 hrs by CellTiter-Glo assay, IC50 = 1.69 μM. 27541357
HEL 92.1.7 Antiproliferative assay 48 hrs Antiproliferative activity against HEL 92.1.7 cells harboring JAK2 V617F mutant after 48 hrs by CellTiter-Glo assay, IC50 = 1.726 μM. 27541357
HL60 Antiproliferative assay Antiproliferative activity against human HL60 cells, IC50 = 1.78 μM. 27541357
PC3 Antiproliferative assay 72 hrs Antiproliferative activity against human PC3 cells after 72 hrs by MTT assay, IC50 = 2.41 μM. 27541357
MDA-MB-231 Antiproliferative assay 72 hrs Antiproliferative activity against human MDA-MB-231 cells after 72 hrs by MTT assay, IC50 = 2.43 μM. 27541357
TAMH Antiproliferative assay 24 hrs Antiproliferative activity against mouse TAMH cells after 24 hrs by CellTiter-Glo assay, IC50 = 3.68 μM. 27541357
MOLM14 Antiproliferative assay 48 hrs Antiproliferative activity against human MOLM14 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 0.079 μM. 28953386
KMS-12-BM Antiproliferative assay 48 hrs Antiproliferative activity against human KMS-12-BM cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 0.75 μM. 28953386
Jurkat Antiproliferative assay Antiproliferative activity against human Jurkat cells, IC50 = 1.09 μM. 28953386
HEL 92.1.7 Antiproliferative assay 36 hrs Antiproliferative activity against human HEL 92.1.7 cells after 36 hrs by PrestoBlue dye based assay, IC50 = 1.17 μM. 28953386
OPM2 Antiproliferative assay 48 hrs Antiproliferative activity against human OPM2 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.21 μM. 28953386
KHYG Antiproliferative assay 48 hrs Antiproliferative activity against human KHYG cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.24 μM. 28953386
KG1 Antiproliferative assay 48 hrs Antiproliferative activity against human KG1 cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.48 μM. 28953386
NKYS Antiproliferative assay 48 hrs Antiproliferative activity against human NKYS cells after 48 hrs by CellTiter-Glo luminescent assay, IC50 = 1.6 μM. 28953386
HL60 Antiproliferative assay Antiproliferative activity against human HL60 cells, IC50 = 1.78 μM. 28953386
AC10 Cytotoxicity assay 24 hrs Cytotoxicity against human AC10 cells assessed as cell viability after 24 hrs by CellTiter-Glo assay, IC50 = 2.02 μM. 28953386
TAMH Cytotoxicity assay 24 hrs Cytotoxicity against TAMH cells assessed as cell viability after 24 hrs by CellTiter-Glo assay, IC50 = 3.68 μM. 28953386
KMS-12-BM Function assay 2 uM 3 hrs Inhibition of JAK2 in IL-6-stimulated human KMS-12-BM cells assessed as suppression of STAT3 phosphorylation at TY705 residue at 2 uM pretreated for 3 hrs followed by IL-6 stimulation by immunoblot method 27541357
MOLM14 Function assay 0.1 uM 3 hrs Inhibition of JAK2 in IL-6-stimulated human MOLM14 cells assessed as suppression of STAT3 phosphorylation at TY705 residue at 0.1 uM pretreated for 3 hrs followed by IL-6 stimulation by immunoblot method 27541357
HEL 92.1.7 Function assay 1 hr Induction of JAK2 V617F mutant phosphorylation at Y1007/8 residues in HEL 92.1.7 cells after 1 hr by immunoblot method 27541357
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 11 mg/mL (23.27 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight
Dilution Calculator Molecular Weight Calculator

In vivo
Batch:

In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 472.58 Formula

C28H32N4O3

 Storage (From the date of receipt)
CAS No. 937272-79-2 Download SDF Storage of Stock Solutions

Synonyms SB1518 Smiles C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2

Mechanism of Action

Features
Dual JAK2/FLT3 inhibitor that has progressed to Phase III clinical trials for treatment of Myelofibrosis.
Targets/IC50/Ki
FLT3 (D835Y)
(Cell-free assay)
6 nM
JAK2 (V617F)
(Cell-free assay)
19 nM
FLT3
(Cell-free assay)
22 nM
JAK2
(Cell-free assay)
23 nM
TYK2
(Cell-free assay)
50 nM
JAK3
(Cell-free assay)
520 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, this compound 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). It effectively permeates cells to modulate signaling pathways downstream of JAK2, whether agonist activated or mutationally activated. This chemical induces apoptosis, cell cycle arrest and antiproliferative effects in JAK2WT- and JAK2V617F-dependent cells. It inhibits cell proliferation of Karpas 1106P and Ba/F3-JAK2V617F with IC50 of 348 and 160 nM, respectively. It 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 ). This compound inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Its 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 this chemical for 3 h leads to a dose-dependent decrease of pFLT3, pSTAT3 and pSTAT5 with an IC50 below 0.5 μM. It induces apoptosis, cell cycle arrest and anti-proliferative effects in FLT3-mutant and FLT3-wt cells. It 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
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.
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. This compound 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). This chemical is efficacious in FLT3-ITD-bearing MV4-11 xenograft models. It 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.
References

Applications

Methods Biomarkers Images PMID
Western blot pFLT3 / FLT3 / pSTAT5 / STAT5 / GAPDH p-STAT3Y705 / STAT3 / ACTIN / PARP pSTAT3 Y705 / STAT3 / β-Tubulin pSTAT3 Y705 / STAT3 / Actin / MAPK / p-AKT S473 / AKT pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin pFLT3(Y591) / pSTAT5(Y694) / pERK1、2 / pAkt(T308) / β-Actin
S8057-WB-1
31102119
Growth inhibition assay Cell viability
S8057-Growth-inhibition-assay-1
29235481
IHC HE staining of liver sections HE staining of skin grafts p-STAT3 / Ki-67 / mCD31 / VEGF-A / Bcl-2
S8057-IHC-1
29785143
Immunofluorescence Phalloidin TUNEL
S8057-IF-1
27334834

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06303193 Not yet recruiting
Myelodysplastic Syndromes
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)
 May 15 2024 Phase 1|Phase 2
NCT06052618 Not yet recruiting
KSHV Inflammatory Cytokine Syndrome (KICS)|Kaposi Sarcoma Herpesvirus -Associated Multicentric Castleman Disease
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)
 May 15 2024 Phase 2
NCT06159491 Not yet recruiting
Chronic Myelomonocytic Leukemia
Douglas Tremblay|Sobi Inc.|Icahn School of Medicine at Mount Sinai
 January 2 2024 Phase 1|Phase 2
NCT05531786 Recruiting
Graft vs Host Disease
National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC)
 March 6 2023 Phase 1|Phase 2

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