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Purity: ≥98%
Ponatinib HCl (AP-24534 HCl; Iclusig), the hydrochloride salt of Ponatinib, is an orally bioavailable and multi-targeted kinase inhibitor approved by the US FDA on December 14, 2012 for the treatment of resistant or intolerant CML and Ph+ ALL. In cell-free assays, it inhibits Abl, PDGFRα, VEGFR2, FGFR1, and Src with IC50 values of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM, respectively. It might be used to treat acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in patients who have the Philadelphia chromosome (Ph+). Ponatinib inhibits both the unmutated and mutated forms of Bcr-Abl, including the highly drug-resistant missense mutation of Bcr-Abl, T315I. Moreover, it inhibits FMS-related tyrosine kinase receptor-3 (Flt3) and tyrosine kinase receptor TIE2.
| Targets |
VEGFR2 (IC50 = 1.5 nM); FGFR1 (IC50 = 2.2 nM); PDGFRα (IC50 = 1.1 nM); Abl (IC50 = 0.37 nM); LYN (IC50 = 0.24 nM); Src (IC50 = 5.4 nM)
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| ln Vitro |
AP24534, with an IC50 of 0.30 nM–2 nM, potently inhibits clinically significant mutants of the Abl kinase domain, including AblT315I and native Abl. Insulin receptor, CDK2/cyclin E, and members of the Aurora kinase family are not inhibited by AP24534. The proliferation of Ba/F3 cells expressing Bcr-Abl with an IC50 of 0.5 nM and Ba/F3 cells expressing a variety of Bcr-Abl mutants with an IC50 of 0.5 nM–36 nM is inhibited by AP24534. Apoptosis induction is correlated with AP24534's inhibition of proliferation. AP24534, with an IC50 of 0.3 nM to 20 nM, potently inhibits receptor phosphorylation and cellular proliferation in leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα receptors. At less than 10 nM, AP24534 inhibits FLT3 signaling and induces apoptosis in MV4-11 (FLT3-ITD(+/+)) AML cells but not in RS4;11 (FLT3-ITD(–/–)) AML cells. Primary leukemic blasts from an AML patient who tests positive for FLT3-ITD are inhibited by AP24534 at an IC50 of 4 nM, but not those from patients whose AML expresses native FLT3.[3] AP24534 potently inhibits FGFR-mediated signaling and viability with an IC50 below 40 nM in Ba/F3 cells engineered to express activated FGFR1-4. AP24534 inhibits FGFR-mediated signaling with an IC50 of less than 40 nM and inhibits cell growth with an IC50 of 7 nM–181 nM in cell lines that represent multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and contain FGFRs dysregulated by a variety of mechanisms.[4]
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| ln Vivo |
AP24534 (2.5 mg/kg and 5 mg/kg) increases mice median survival in a mouse xenograft model of Ba/F3 cells expressing native Bcr-Abl. AP24534 (10 mg/kg–50 mg/kg) dramatically inhibits tumor growth in the Ba/F3 Bcr-AblT315I xenograft model. AP24534 (30 mg/kg) reduces the amounts of phosphorylated CrkL and Bcr-Abl in the tumors.
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| Enzyme Assay |
The impact of AP24534 (0-320 nM) on the activity of GST-Abl kinase is measured with a synthetic peptide substrate (Abltide: EAIYAAPFAKKK). In 25 μL reaction mixture, assays are run for 15 minutes at 30 °C. The following were used: 8 mM MOPS (pH 7), 0.2 mM EDTA, 50 μM Abltide, 30 mM MgCl2, 10 mM β-glycerol phosphate, 1 mM EGTA, 0.002% Brij-35, 0.4 mM DTT, 0.2 mg/mL BSA, 0.4 mM sodium orthovanadate, 10 nM WT or mutant GST-Abl kinase, and 100 µM ATP/γ-32[P]ATP (5000 cpm/pmol). Transferring a part of the reaction mixture onto a p81 phosphocellulose filter and submerging it in 0.75% phosphoric acid is how reactions are stopped. Phosphate incorporation is assessed using scintillation counting after filters are air dried and cleaned three times in 0.75% phosphoric acid. After removing the peptide substrate from the kinase reaction, all data are adjusted for background binding to the filters. Kinase experiments come first, followed by time course studies to determine the linear range of enzymatic activity.
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| Cell Assay |
Ba/F3 cell lines are arranged in 96-well plates (4 × 103 cells/well) and given a 72-hour incubation period with AP24534. A methanethiosulfonate (MTS)-based viability assay (CellTiter96 Aqueous One Solution) is used to measure proliferation. Every value is compared to the drug-free control wells. The mean of three separate, quadruplicat experiments is used to report IC50 values.
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| Animal Protocol |
Mouse xenograft models of Ba/F3 cells expressing Bcr-Abl or Bcr-AblT315I
2.5 mg/kg and 5 mg/kg for Ba/F3 Bcr-Abl; 2.5 mg/kg–50 mg/kg for Ba/F3 Bcr-AblT315I Oral gavage once daily |
| References |
| Molecular Formula |
C29H28CLF3N6O
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|---|---|
| Molecular Weight |
569.03
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| Exact Mass |
568.1965217
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| Elemental Analysis |
C, 61.21; H, 4.96; Cl, 6.23; F, 10.02; N, 14.77; O, 2.81
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| CAS # |
1114544-31-8
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| Related CAS # |
Ponatinib;943319-70-8
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5.Cl
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| InChi Key |
BWTNNZPNKQIADY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H27F3N6O.ClH/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37;/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39);1H
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| Chemical Name |
3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide;hydrochloride
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| Synonyms |
AP-24534 HCl; AP24534; AP 24534 HCl; Trade name: Iclusig
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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 |
| 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: ≥ 2.5 mg/mL (4.39 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.5 mg/mL (4.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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: ≥ 2.5 mg/mL (4.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL (for HCl salt) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7574 mL | 8.7869 mL | 17.5738 mL | |
| 5 mM | 0.3515 mL | 1.7574 mL | 3.5148 mL | |
| 10 mM | 0.1757 mL | 0.8787 mL | 1.7574 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 |
| NCT03934372 | Recruiting | Drug: Ponatinib | Leukemia Lymphoma |
Incyte Biosciences International Sàrl |
January 29, 2020 | Phase 1 Phase 2 |
| NCT05306301 | Recruiting | Drug: Ponatinib | Chemotherapy Leukemia, Acute Lymphoblastic |
Gruppo Italiano Malattie EMatologiche dell'Adulto |
October 5, 2022 | Phase 2 |
| NCT02428543 | Active Recruiting |
Drug: Ponatinib & Cytarabine | Acute Myeloid Lukemia | Versailles Hospital | July 2013 | Phase 1 Phase 2 |
| NCT02776605 | Active Recruiting |
Drug: Prednisone Drug: Ponatinib |
ALL | PETHEMA Foundation | June 2016 | Phase 2 |
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