| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
EGFR/HER2
Tarloxotinib targets EGFR and HER2 (ErbB family) as a pan-ErbB inhibitor. It is a hypoxia-activated prodrug; under hypoxic conditions, it is metabolized to release the active effector tarloxotinib-E, which irreversibly inhibits EGFR, HER2, and HER4 with IC50 values of <1 nM. The prodrug itself is pharmacologically inert in normoxic conditions. |
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| ln Vitro |
Tarloxotinib bromide is demonstrated to be metabolized efficiently under hypoxia using a panel of human NSCLC cell lines (rate of TKI release 0.4-2.1 nM/hr/106 cells), a process that is inhibited by oxygen (TKI release <0.002 nM/hr/106 cells), in order to confirm the mechanism of action. Tarloxotinib bromide activity is reduced 14–80 fold compared to TKI in cellular anti-proliferative and receptor phosphorylation assays. Hyperbaric oxygen breathing, as opposed to air breathing controls, suppresses the release of TKI from tarloxotinib bromide by >80% (538 vs. 99 nM/kg; p<0.01) using PC9 tumors. The combined information confirms that tarloxotinib bromide is an irreversible EGFR-TKI that is activated by hypoxia and indicates that it is more active than erlotinib[2]. |
| ln Vivo |
Tarloxotinib bromide activity against each EGFR-TKI is benchmarked using a prototypic WT EGFR driven xenograft model (A431), which is created by "retrotranslation" of reported plasma exposure for each agent in human subjects back to the xenograft model. Tumor regression and long-lasting suppression of WT EGFR tumor phosphorylation are only linked to treatment with clinically relevant doses and schedules of tarloxotinib bromide. In agreement with these results, treatment with taroxotinib bromide has also been shown to regress the WT EGFR NSCLC tumor models H125 and H1648, indicating that taloxotinib bromide offers the required therapeutic index to inhibit WT EGFR in vivo[1]. |
| Enzyme Assay |
Tarloxotinib is a hypoxia-activated prodrug; its activation is assessed by measuring the rate of TKI release under hypoxic vs. normoxic conditions in NSCLC cell lines. The active effector's kinase inhibition is confirmed via cell-free enzyme assays measuring EGFR, HER2, and HER4 activity with IC50 <1 nM. Receptor binding is characterized by irreversible covalent inhibition of the kinase domain.
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| Cell Assay |
In vitro cell-based assays use human NSCLC cell lines to measure hypoxia-dependent TKI release. Cellular anti-proliferative and receptor phosphorylation assays compare prodrug activity to active TKI. Ba/F3 cell models with EGFR exon 20 insertions and HER2 mutants are used to determine effector potency (IC50 <5 nM). Activity is benchmarked against standard EGFR-TKIs like erlotinib.
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| Animal Protocol |
In vivo efficacy is evaluated using subcutaneous xenograft models, including WT EGFR-driven A431 tumors and NSCLC models H125 and H1648. Human tumor xenografts (e.g., CUTO14, CUTO17, HCC-1954) in nude mice are used to assess tumor growth inhibition. The MB49 syngeneic model is used to study combinations with immune checkpoint inhibitors. Hyperbaric oxygen studies confirm hypoxia-dependent activation in vivo.
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| ADME/Pharmacokinetics |
Tarloxotinib bromide has a molecular weight of 681.77 g/mol and formula C₂₄H₂₄Br₂ClN₉O₃. It is soluble in DMSO (33 mg/mL) and can be formulated for in vivo use in 10% DMSO+40% PEG300+5% Tween 80+45% Saline. Pharmacokinetic analysis confirms markedly higher levels of tarloxotinib-E in tumor tissue than in plasma or skin. The prodrug is designed to minimize systemic exposure to the active effector.
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| Toxicity/Toxicokinetics |
Toxicity is minimized by the hypoxia-activated prodrug design, which reduces systemic exposure to the active EGFR/HER2 inhibitor. Preclinical studies show a favorable therapeutic index, enabling tumor regression without the systemic toxicity associated with conventional TKIs. Hyperbaric oxygen studies demonstrate that suppressing TKI release reduces toxicity.
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| References |
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| Additional Infomation |
Tarloxotinib bromide (TH-4000, PR-610) is a clinical-stage hypoxia-activated pan-HER kinase inhibitor. Phase 2 data (NCT03805841) showed a 22% partial response and 44% stable disease in HER2-mutant NSCLC. It is designed to treat EGFR exon 20 and HER2-mutant solid tumors. The compound is a prodrug that releases a covalent, irreversible pan-ErbB inhibitor selectively in hypoxic tumors. It has also been studied in combination with immune checkpoint inhibitors.
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| Molecular Formula |
C24H24BR2CLN9O3
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|---|---|
| Molecular Weight |
681.766860961914
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| Exact Mass |
679.005
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| Elemental Analysis |
C, 42.28; H, 3.55; Br, 23.44; Cl, 5.20; N, 18.49; O, 7.04
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| CAS # |
1636180-98-7
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| Related CAS # |
1636938-13-0 (cation);1636180-98-7 (bromide);
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| PubChem CID |
51038315
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
39
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| Complexity |
863
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1=C(C=CC(=C1)NC1C2C(=CN=C(C=2)NC(/C=C/C[N+](C)(C)CC2=C([N+](=O)[O-])N=CN2C)=O)N=CN=1)Cl.[Br-]
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| InChi Key |
WAKIMVYUBWMMHJ-FXRZFVDSSA-N
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| InChi Code |
InChI=1S/C24H23BrClN9O3.BrH/c1-33-14-30-24(34(37)38)20(33)12-35(2,3)8-4-5-22(36)32-21-10-16-19(11-27-21)28-13-29-23(16)31-15-6-7-18(26)17(25)9-15;/h4-7,9-11,13-14H,8,12H2,1-3H3,(H-,27,28,29,31,32,36);1H/b5-4+;
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| Chemical Name |
[(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide
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| Synonyms |
TH-4000; TH 4000; TH4000; PR-610; PR610; PR 610; Tarloxotinib bromide; Hypoxin; Tarloxotinib
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO: ≥ 33 mg/mL (~48.4 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.67 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 (3.67 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4668 mL | 7.3339 mL | 14.6677 mL | |
| 5 mM | 0.2934 mL | 1.4668 mL | 2.9335 mL | |
| 10 mM | 0.1467 mL | 0.7334 mL | 1.4668 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 |
| NCT03805841 | Terminated | Drug: tarloxotinib bromide | NRG1 Fusion ERBB Fusion |
Rain Oncology Inc | March 13, 2019 | Phase 2 |
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