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Purity: ≥98%
Pacritinib (formerly also known as SB-1518; SB1518; trade name Vonjo) is a novel, potent, selective, and orally bioavailable inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with potential antitumor activity. As of Feb 2022, the US FDA has approved pacritinib for the treatment of patients with myelofibrosis and severe thrombocytopenia. It inhibits JAK2 and FLT3 with IC50s of 23 and 22 nM in cell-free assays, respectively. Pacritinib also inhibits FLT3D835Y (FLT3's mutant form) with an IC50 of 6 nM. Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders.
| ln Vitro |
Pacritinib (SB1518) has two times the potency against TYK2 (IC50=50 nM), 23 times the potency against JAK3 (IC50=520 nM), and 56 times the potency against JAK1 (IC50=1280 nM) in comparison to JAK2. When tested against 100 nM Pacritinib at adenosine triphosphate comparable concentrations to its Michaelis constant (Km), the remaining assessed kinases exhibit <30% inhibition. With an IC50 of 47 and 67 nM, respectively, paritinib inhibits MV4-11 and MOLM-13 cells, which are cell lines generated from human acute myeloid leukemias caused by a FLT3 ITD mutation. The JAK2 signaling-dependent cell lines Karpas 1106P and Ba/F3-JAK2V617F are inhibited by paritinib with IC50 values of 348 and 160 nM, respectively. accordingly[1]. MV4-11 cells bearing FLT3-ITD are treated for three hours at varying dosages of pacritinib (SB1518), and the amounts of pFLT3, pSTAT5, and pERK1/2 are measured. pFLT3, pSTAT5, pERK1/2, and pAkt all show dose-dependent decreases in response to paritinib, with IC50 values of 80, 40, 33, and 29 nM, respectively. When compared to FLT3-ITD in MV4-11 and MOLM-13 cells, the IC50 on auto-phosphorylation of FLT3-wt in RS4;11 is four times greater (IC50=600 nM). Nevertheless, STAT5 inhibition is observed at significantly lower Pacritinib concentrations (IC50=8 nM)[2].
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| ln Vivo |
In the Ba/F3-JAK2V617F engraftment model, mice are dosed with 50 or 150 mg/kg poqd of pacritinib (SB1518) for 13 days, beginning 4 days after cell inoculation, in order to assess the drug's effectiveness. When the trial comes to an end, the vehicle control mice had hepatomegaly (1.3 fold) and splenomegaly (~7 fold), which are similar to the symptoms of symptomatic myelofibrosis patients. When administered at 150 mg/kg poqd, SB1518 therapy dramatically reduces all of these symptoms, resulting in a 60% (± 9%) normalization of spleen weight and a 92% (± 5%) normalization of liver weight. It is also well tolerated, causing minimal weight loss and no hematological toxicities, such as anemia or thrombocytopenia[1]. After a single oral administration of 10 mg/kg, pacritinib (SB1518) in rats exhibits moderately quick absorption (tmax=4 h), with a peak concentration of 114 ng/mL, an AUC of 599 ng·h/mL, and a terminal half-life of approximately 6 h. After a single oral dose of 3 mg/kg, dogs absorb pacritinib (SB1518) fast (tmax=2.0 h), peaking at ~12 ng/mL, with an AUC of 53 ng·h/mL and a terminal half-life of 3.4 h[3].
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following oral administration of 200mg pacritinib twice daily, the mean Cmax and AUC0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively. The Tmax is approximately 4-5 hours post-dose. Co-administration with food does not significantly impact the pharmacokinetics of pacritinib. Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine. Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity excreted in the urine. The mean apparent volume of distribution of pacritinib at steady-state is 229 L. The mean apparent clearance of pacritinib is 2.09 L/h. Metabolism / Metabolites Pacritinib metabolism is mediated primarily by CYP3A4. While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M4 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity. The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, respectively. Biological Half-Life The mean effective half-life of pacritinib is 27.7 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity
In the published preregistration clinical trials of pacritinib, rates of serum ALT elevations were not provided, and no mention of ALT elevations are given in the product label or FDA review of efficacy and safety for its approval. Nevertheless, rates of ALT or AST elevations in several small clinical trials were said to be 15%, with 6% being above 5 times the upper limit of normal (ULN). Since its approval and more widespread clinical use, there have been no reports of serum enzyme or bilirubin elevations or instances of clinically apparent liver injury associated with the use of pacritinib, but it has been clinically available for a short time only. Likelihood score: E* (unproven, but possible cause of clinically apparent liver injury including reactivation of hepatitis B). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of pacritinib during breastfeeding. The manufacturer recommends that breastfeeding be withheld during therapy and for 2 weeks after the last dose. An alternate drug is preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Pacritinib is 98.8% protein-bound in plasma. |
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| Additional Infomation |
Pharmacodynamics
Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min). Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials. A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout therapy. |
| Molecular Formula |
C28H32N4O3
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| Molecular Weight |
472.58
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| Exact Mass |
472.247
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| CAS # |
937272-79-2
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| Related CAS # |
Pacritinib hydrochloride;1228923-43-0
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| PubChem CID |
46216796
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
711.4±70.0 °C at 760 mmHg
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| Flash Point |
384.0±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.574
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| LogP |
4.23
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
35
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| Complexity |
644
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CCN(C1)CCOC2=C3COC/C=C/COCC4=CC(=CC=C4)C5=NC(=NC=C5)NC(=C3)C=C2
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| InChi Key |
HWXVIOGONBBTBY-ONEGZZNKSA-N
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| InChi Code |
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+
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| Chemical Name |
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
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1 mg/mL (2.12 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.3 mg/mL (0.63 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06159491 | Not yet recruiting | Drug: Pacritinib Drug: Azacitidine |
Chronic Myelomonocytic Leukemia |
Douglas Tremblay | January 2, 2024 | Phase 1 Phase 2 |
| NCT02765724 | Completed | Drug: Pacritinib | Myelofibrosis | CTI BioPharma | January 2015 | Phase 1 |
| NCT05552183 | Recruiting | Drug: oral dose of 200 mg pacritinib twice daily (BID) |
Hepatic Impairment | CTI BioPharma | December 12, 2022 | Phase 1 |
| NCT04858256 | Recruiting | Drug: Pacritinib | T-Cell Neoplasm Lymphoproliferative Disorders |
University of Michigan Rogel Cancer Center |
March 29, 2023 | Phase 2 |
Pacritinib effectively blocks FLT3 signaling in FLT3-ITD (MV4-11, MOLM-13) or FLT3-wt (RS;4-11) cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib is efficacious in xenografts derived from cell lines harboring FLT3-ITD.Blood Cancer J.2011Nov;1(11):e44. |
Activated JAK2 signaling in MV4-11 cells after selective inhibition of FLT3 induces FLT3-TKI resistance.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib induces cell cycle arrest and apoptosis in FLT3-ITD- (MV4-11, MOLM-13) and FLT3-wt- (RS;4-11) harboring cancer cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib inhibits proliferation of AML cells with highest potency in FLT3-ITD harboring cells.Blood Cancer J.2011Nov;1(11):e44. |
Pacritinib blocks proliferation and induces apoptosis inex vivoexpanded primary AML blast cells.Blood Cancer J.2011Nov;1(11):e44. |
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