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5mg |
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25mg |
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50mg |
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100mg |
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Brigatinib (formerly AP26113; AP-26113; ALK-IN-1; trade name: Alunbrig) is an orally bioavailable, FDA-approved and selective ALK (anaplastic lymphoma kinase) inhibitor with potential antineoplastic activity. In a cell-free assay, it inhibits ALK with an IC50 of 0.62 nM. In 2017, the FDA approved brgatinib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK), who have progressed or are intolerant to crizotinib. It was shown that brgatinib could overcome the L1196M mutation-mediated crizotinib resistance. A tyrosine kinase receptor called anaplastic lymphoma kinase (ALK) has been linked to a number of solid and hematologic malignancies. ALK mutations are found in roughly 5–7% of cases of neuroblastoma; however, in the group of patients who relapse, the percentage of ALK-positive patients rises noticeably. An analog of AP26113 binds to EGFR and its mutant forms, inhibiting EGFR as well as ALK kinase and ALK fusion proteins. This inhibits the signaling pathways of ALK kinase and EGFR kinase, which in turn prevents tumor cell growth in tumor cells that are vulnerable to it. Currently undergoing evaluation in a global phase 2 registration trial, brgatinib is the most clinically advanced phosphine oxide-containing drug candidate to date.
Targets |
ALK (IC50 = 0.37 nM); ROS1 (IC50 = 1.9 nM); FLT3 (IC50 = 2.1 nM); IGF1R (IC50 = 24.9 nM); EGFR(C797S/del19) (IC50 = 39.9 nM)
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ln Vitro |
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ln Vivo |
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Enzyme Assay |
A HotSpotSM kinase profile of 289 kinases is carried out in vitro. The experiment is carried out with brigatinib concentrations ranging from 0.05 nM to 1 μM in the presence of 10 μM [33P]-ATP.
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Cell Assay |
The specified inhibitors are serially diluted and added to each well containing 15,000 cells. Resazurin measures the viability of the cells after 72 hours. By fitting data to an equation of log (inhibitor concentration) vs. normalized response (variable slope), IC50 values are determined using GraphPad Prism 6.0. Every experiment is carried out in two copies and at least three times.
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Animal Protocol |
Mice: (1) Female SCID/beige mice, aged eight to ten weeks, receive intravenous injections of 5x106 H3122 cells each. After the tumor size reaches approximately 300 mm3 on day zero, the mice are randomized into ten treatment groups. Treatments are taken orally at a dose volume of 10 mL/kg for a maximum of 21 days in a row. Tumors under the skin are measured twice or three times a week. The formula (L×W2)/2 is used to calculate the tumor volume (in mm3). The animal is put to sleep by CO2 asphyxiation when a tumor weighs 10% of its body weight. (2) Female SCID/beige mice, aged eight to ten weeks, receive subcutaneous injections of 2.5 ×106 Karpas-299 cells per mouse. After the tumors reach approximately 180 mm3 on day zero, the mice are randomly assigned to one of ten treatment groups. Oral treatment is given for 14 days in a row at a dose volume of 10 mL/kg. The measurement and computation of tumor volume follow the guidelines for the H3122 model.
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References |
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Molecular Formula |
C₂₉H₃₉CLN₇O₂P
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Molecular Weight |
584.09
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Exact Mass |
583.26
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Elemental Analysis |
C, 59.63; H, 6.73; Cl, 6.07; N, 16.79; O, 5.48; P, 5.30
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CAS # |
1197953-54-0
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Related CAS # |
Brigatinib-13C6
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Appearance |
Light yellow solid powder
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SMILES |
CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC
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InChi Key |
AILRADAXUVEEIR-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)
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Chemical Name |
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine
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Synonyms |
AP-26113; AP 26113; Brigatinib-analog; AP26113; Brigatinib; Alunbrig.
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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: ≥ 1 mg/mL (1.71 mM) (saturation unknown) in 10% EtOH + 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 EtOH 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 (1.71 mM) (saturation unknown) in 10% EtOH + 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 10.0 mg/mL clear EtOH 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: ≥ 1 mg/mL (1.71 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 0.5 mg/mL (0.86 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 5.0 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 5: ≥ 0.5 mg/mL (0.86 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 5.0 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. Solubility in Formulation 6: ≥ 0.5 mg/mL (0.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 7: NMP+polyethylene glycol 300 (10+90, v+v): 1 mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.7121 mL | 8.5603 mL | 17.1206 mL | |
5 mM | 0.3424 mL | 1.7121 mL | 3.4241 mL | |
10 mM | 0.1712 mL | 0.8560 mL | 1.7121 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 |
NCT04223596 | Active Recruiting |
Drug: Brigatinib | Lung Cancer NSCLC |
Fundación GECP | May 4, 2020 | Phase 2 |
NCT03535740 | Active Recruiting |
Drug: Brigatinib | ALK-positive Advanced NSCLC | Ariad Pharmaceuticals | January 31, 2019 | Phase 2 |
NCT03596866 | Active Recruiting |
Drug: Brigatinib Drug: Alectinib |
ALK+ Advanced NSCLC | Takeda | April 19, 2019 | Phase 3 |
NCT04074993 | Active Recruiting |
Drug: Brigatinib | Non Small Cell Lung Cancer | JI-YOUN HAN | May 15, 2020 | Phase 2 |
NCT05361564 | Not yet recruiting | Drug: Brigatinib | Non-small Cell Lung Cancer | Yonsei University | June 2022 | Phase 2 |
Two different ALK kinase inhibitors, NVP-TAE684 and AP26113, overcome crizotinib resistance in H3122 CR cells. Proc Natl Acad Sci U S A. 2011 May 3; 108(18): 7535–7540. |
Effect of brigatinib in a xenograft neuroblastoma model.Oncotarget.2016 May 17;7(20):29011-22. td> |
Effect of brigatinib on ALK gain-of-function rough eye phenotypes in aDrosophilaALK model.Oncotarget.2016 May 17;7(20):29011-22. td> |