| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 100mg |
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| 250mg | |||
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| Targets |
Enbezotinib primarily targets the Rearranged during Transfection (RET) receptor tyrosine kinase and SRC kinase. It demonstrates potent activity against wild-type RET, multiple RET fusion variants, and clinically relevant solvent-front resistance mutations including G810R, G810C, and G810S. The compound spares VEGFR2/KDR, achieving a >100-fold selectivity window that eliminates hypertension-related off-target effects commonly associated with multi-kinase inhibitors.
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| ln Vitro |
Compound 5 (enbezotinib) (0.3-300 nM) inhibits p-RET (y905) in cells triggered by RET [1].
Enbezotinib exhibits low nanomolar potency against wild-type RET and 18 RET mutations/fusions, maintaining IC50 values of 1-17 nM across these targets. It potently inhibits RET autophosphorylation. The compound shows broad-spectrum activity against various cancers driven by RET alterations. Enbezotinib demonstrates potent activity against solvent-front mutations that confer clinical resistance to earlier approved agents, addressing a critical research gap for resistance modeling. |
| ln Vivo |
Embetinib (Compound 5) decreases the growth of tumors in mice when given twice daily for 27 days at a dose of 2–5 mg/kg [1].
In vivo, enbezotinib exerts anti-tumor activity through potent and selective inhibition of RET and SRC kinases. Upon oral administration, it specifically targets and binds to RET mutants and RET-containing fusion products, resulting in inhibition of tumor cell growth. The compound has demonstrated efficacy in drug-resistant and naïve RET-driven cancer models. Its favorable pharmacokinetic properties and broad-spectrum activity support its potential as a precision therapy for RET-altered cancers. |
| Enzyme Assay |
The enzymatic activity of enbezotinib is typically assessed using kinase inhibition assays with recombinant RET and SRC proteins. Assays are performed in kinase buffer containing ATP and a peptide substrate, with compound incubated at varying concentrations. Phosphorylation is measured using homogeneous time-resolved fluorescence (HTRF) or radiometric methods. IC50 values are calculated from dose-response curves. The assay panel includes wild-type RET, RET fusion variants, and solvent-front mutants (G810R/C/S) to evaluate potency against resistance-associated mutations.
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| Cell Assay |
Cellular activity of enbezotinib is evaluated in RET-driven cancer cell lines, such as those harboring RET fusions or mutations. Cells are treated with escalating concentrations of the compound for 48-72 hours. Cell viability is measured using CellTiter-Glo or MTT assays to determine IC50 values. RET autophosphorylation and downstream signaling (e.g., ERK, AKT) are assessed by Western blot. The compound's ability to inhibit cell proliferation in both drug-naïve and drug-resistant RET-mutant models is evaluated.
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| Animal Protocol |
In vivo efficacy of enbezotinib is evaluated in xenograft mouse models bearing RET-driven tumors. Tumor-bearing mice are administered enbezotinib orally at various doses, typically once or twice daily. Tumor volume is measured bi-weekly using calipers, and tumor growth inhibition (TGI) is calculated. Pharmacodynamic endpoints include assessment of RET phosphorylation in tumor tissues by immunohistochemistry or Western blot. Body weight and clinical signs are monitored for tolerability. Efficacy is compared against vehicle control and standard-of-care RET inhibitors.
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| ADME/Pharmacokinetics |
Enbezotinib demonstrates favorable pharmacokinetic properties with oral bioavailability. It is designed as a macrocyclic inhibitor with a molecular weight of 424.43 Da (C21H21FN6O3). The compound is soluble in DMSO (100 mg/mL). Its VEGFR2-sparing kinome selectivity contributes to a favorable safety profile by avoiding hypertension-related side effects. The SWORD-1 first-in-human trial evaluated the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of enbezotinib in adult patients with advanced solid tumors harboring RET alterations.
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| Toxicity/Toxicokinetics |
Preclinical toxicity data for enbezotinib indicate a favorable safety profile with minimal off-target effects due to its selective RET/SRC inhibition and VEGFR2-sparing特性. The compound is designed to overcome resistance to first- and second-generation EGFR inhibitors while minimizing off-target effects. In preclinical studies, the compound was well-tolerated with no obvious toxicity at efficacious doses. Further toxicological evaluation is ongoing in clinical development.
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| References | |
| Additional Infomation |
Enbezotinib is a highly bioavailable, selective dual inhibitor that inhibits fusions and mutations involving proto-oncogene receptor tyrosine kinases (RET) and Src family tyrosine kinases, exhibiting potential antitumor activity. After oral administration, entbezotinib specifically targets and binds to RET mutants and RET-containing fusion products. This leads to the inhibition of growth in tumor cells with enhanced RET activity. By inhibiting Src kinase-mediated signaling pathways and reducing the recruitment of multiple receptor tyrosine kinases involved in bypass resistance initiated by Src, entbezotinib may overcome tumor resistance, thereby enhancing its therapeutic efficacy. RET overexpression, activating mutations, and fusions lead to upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types; dysregulation of RET activity plays a crucial role in the development and progression of these cancers. Src tyrosine kinases are upregulated in various tumor cells and play important roles in tumor cell proliferation, survival, migration, invasion, and angiogenesis. Upregulation of Src expression has also been observed in tumors resistant to RET inhibitors.
Enbezotinib (also known as TPX-0046) is a next-generation RET/SRC inhibitor that retains activity against solvent-front mutations (G810R/C/S) which cause resistance to first-generation RET inhibitors. Its macrocyclic scaffold enables potent activity against a broad spectrum of RET alterations. The dual RET/SRC inhibition strategy allows study of SRC-mediated bypass resistance mechanisms. The compound is in clinical development for RET-altered cancers, with the SWORD-1 trial evaluating its safety and efficacy. |
| Molecular Formula |
C21H21FN6O3
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|---|---|
| Molecular Weight |
424.43
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| Exact Mass |
424.17
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| Elemental Analysis |
C, 59.43; H, 4.99; F, 4.48; N, 19.80; O, 11.31
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| CAS # |
2359649-81-1
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| Related CAS # |
Enbezotinib (enantiomer);2359650-19-2
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| PubChem CID |
146662764
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| Appearance |
White to off-white solid powder
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| LogP |
1.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
31
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| Complexity |
702
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O1C2=NC=C(F)C=C2CN2[C@]3([H])CCC[C@]3([H])OC3=CN4C(N=C23)=C(C=N4)C(=O)NC[C@@H]1C
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| InChi Key |
BYYQDEOVMILBQT-XZJROXQQSA-N
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| InChi Code |
InChI=1S/C21H21FN6O3/c1-11-6-23-20(29)14-8-25-28-10-17-19(26-18(14)28)27(15-3-2-4-16(15)31-17)9-12-5-13(22)7-24-21(12)30-11/h5,7-8,10-11,15-16H,2-4,6,9H2,1H3,(H,23,29)/t11-,15+,16-/m0/s1
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| Chemical Name |
(13E,14E,15aR,18aS,5S)-35-Fluoro-5-methyl-15,15a,16,17,18,18a-hexahydro-4-oxa-7-aza-1(5,3)-cyclopenta[b]pyrazolo[1',5':1,2]pyrimido[4,5-e][1,4]oxazina-3(3,2)-pyridinacyclooctaphan-8-one
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| Synonyms |
TPX-0046; TPX 0046; 2359649-81-1; Enbezotinib [INN]; F6EVK907XR; RefChem:136748; TPX0046; Enbezotinib;
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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) |
DMSO : ~100 mg/mL (~235.61 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.90 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 20.8 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: ≥ 2.08 mg/mL (4.90 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3561 mL | 11.7805 mL | 23.5610 mL | |
| 5 mM | 0.4712 mL | 2.3561 mL | 4.7122 mL | |
| 10 mM | 0.2356 mL | 1.1781 mL | 2.3561 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.
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