| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
Axl (IC50 = 0.7 nM); Mer (IC50 = 1 nM); FLT3 (IC50 = 147 nM)
AXL and Mer (TAM family receptor tyrosine kinases) - dual inhibitor (Axl IC50 = 0.7 nM; Mer IC50 = 1.0 nM). |
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| ln Vitro |
ONO-7475 is a MER Tyrosine Kinase and Anexelekto inhibitor with excellent selectivity. FLT3-ITD AML cells are killed or grown arrested by ONO-7475. In MOLM13 cells, AraC and p53 reduction enhance ONO-7475-induced apoptosis. In FLT3-ITD but not WT FLT3 AML cells, inhibition of AXL suppresses survival and proliferation signaling and induces apoptotic proteins.[1] ONO-7475 increases the susceptibility of EGFR-mutant NSCLC cells overexpressing AXL to the EGFR-TKIs dacomitinib and osimertinib. Furthermore, ONO-7475 inhibits the development and upkeep of cells that are tolerant to EGFR-TKI.[2]
In vitro studies demonstrate that Tamnorzatinib is a potent and selective inhibitor of Axl and Mer receptor tyrosine kinases, with IC50 values of 0.7 nM and 1.0 nM, respectively. Axl and Mer are members of the TAM family of receptor tyrosine kinases, which play important roles in cancer cell survival, proliferation, migration, and immune evasion. By inhibiting Axl and Mer, Tamnorzatinib blocks downstream signaling pathways (such as PI3K/AKT and MAPK/ERK) and induces apoptosis in cancer cells. The compound can effectively inhibit the growth of FLT3-ITD mutations in acute myeloid leukemia and induce apoptosis. |
| ln Vivo |
ONO-7475 is efficient when used with MOLM13 cells in a murine in vivo xenograft model. Using an AML xenograft model, ONO-7475 increases the length of mouse survival while inhibiting AML cell infiltration in the liver. It is appropriate to pursue ONO-7475's clinical development as a treatment for AML because it is effective.[1] Treatment with an initial combination of osimertinib and ONO-7475 significantly reduces tumor growth and delays tumor recurrence in xenograft models of AXL-overexpressing EGFR mutated lung cancer.[2]
In vivo studies have demonstrated that Tamnorzatinib is orally bioavailable and has anticancer activity. The compound makes AXL-overexpressing EGFR-mutant NSCLC cells sensitive to EGFR-TKIs, inhibiting the generation and maintenance of resistant cells. By targeting Axl and Mer, Tamnorzatinib may overcome resistance to EGFR-TKIs and other targeted therapies in cancer patients. The compound's oral bioavailability and potent inhibition of Axl and Mer make it a promising candidate for cancer therapy, particularly in combination with other targeted agents or immunotherapies. Further studies are needed to fully characterize the compound's efficacy in various cancer models. |
| Enzyme Assay |
Kinase activity assays are performed using purified recombinant Axl and Mer kinases and suitable peptide substrates, along with ATP. The enzymes are incubated with the substrates and varying concentrations of Tamnorzatinib, and kinase activity is measured using radioactive ATP incorporation or fluorescence-based detection methods. IC50 values are calculated from dose-response curves. Selectivity over other kinases is assessed using similar biochemical assay formats or by screening against kinase panels to confirm the compound's specificity for Axl and Mer.
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| Cell Assay |
For 48 hours, MOLM13, MV4;11 (FLT3 ITD), and OCI-AML3 (FLT3 WT) cells are cultured with either a vehicle (0.1% DMSO) or different dosages of ONO-7475. Flow cytometry is used to quantify apoptosis and the number of viable cells.
Cellular assays for Tamnorzatinib typically involve culturing cancer cell lines that express Axl and/or Mer, such as AML cell lines or NSCLC cell lines. Cells are treated with the compound at various concentrations, and cell viability is assessed using MTT or CellTiter-Glo assays. Axl and Mer phosphorylation and downstream signaling (AKT, ERK) are assessed by Western blotting. Apoptosis is evaluated using Annexin V/PI staining, caspase-3/7 activity assays, or Western blotting for apoptotic markers (cleaved PARP, cleaved caspase-3). Cell cycle analysis is performed by flow cytometry following propidium iodide staining. The compound's ability to sensitize cells to EGFR-TKIs is assessed in combination studies. |
| Animal Protocol |
4-week old female NSG mice bearing MOLM13 cells
6 mg/kg, 20 mg/kg Oral gavage In vivo efficacy of Tamnorzatinib is evaluated in mouse xenograft models using cancer cell lines, including AML and NSCLC models. Tumor-bearing mice are treated with Tamnorzatinib via oral administration, and tumor volume is monitored over time. The compound's ability to inhibit tumor growth and sensitize tumors to EGFR-TKIs is assessed in combination studies. Endpoints include tumor growth inhibition, assessment of Axl and Mer phosphorylation in tumor tissues by immunohistochemistry or Western blotting, and evaluation of apoptosis and proliferation markers. Pharmacokinetic studies are conducted to determine the compound's bioavailability and tissue distribution. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Tamnorzatinib have been characterized to support its use as an orally active research tool and potential therapeutic agent. The compound has a molecular weight of 562.57 and the molecular formula C32H26N4O6. Key PK parameters including half-life, clearance, volume of distribution, and oral bioavailability are determined using LC-MS/MS analysis of plasma and tissue samples following oral administration. The compound's ability to reach tumors and maintain therapeutic concentrations is important for its efficacy in cancer models. The compound should be stored as a powder at -20°C.
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| Toxicity/Toxicokinetics |
Toxicological evaluation of Tamnorzatinib is typically conducted in parallel with efficacy studies in animal models. Standard toxicology assessments include in vitro cytotoxicity assays against a panel of normal and cancer cell lines to determine the compound's selectivity index. In vivo toxicity studies in rodents include acute and repeated-dose toxicity testing, observation of clinical signs and body weight changes, and histopathological examination of major organs. As an Axl/Mer inhibitor that affects cancer cell survival and proliferation, potential effects on normal tissues that express Axl and Mer, such as the immune system and reproductive organs, are carefully monitored.
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| References | |
| Additional Infomation |
Tamnorzatinib is an orally administered selective receptor tyrosine kinase (RTK) inhibitor that inhibits Axl (UFO) and Mer, exhibiting potential antitumor activity. Upon administration, Tamnorzatinib targets and binds to Axl and Mer, inhibiting their activity. This blocks Axl and Mer-mediated signal transduction pathways, suppressing the proliferation and migration of Axl and Mer-overexpressing tumor cells. Axl and Mer both belong to the TAM (Tyro3, Axl, and Mer) family of RTKs and are overexpressed in various tumor cell types. They play crucial roles in tumor cell proliferation, survival, invasion, angiogenesis, and metastasis, and their expression is associated with drug resistance and poor prognosis.
Tamnorzatinib (ONO-7475) is an orally bioavailable small-molecule dual inhibitor of the TAM family receptor tyrosine kinases Axl and Mer. The compound inhibits Axl with an IC50 of 0.7 nM and Mer with an IC50 of 1.0 nM. Tamnorzatinib can effectively inhibit the growth of FLT3-ITD mutations in acute myeloid leukemia and induce apoptosis. The compound also makes AXL-overexpressing EGFR-mutant NSCLC cells sensitive to EGFR-TKIs, inhibiting the generation and maintenance of resistant cells. Tamnorzatinib is not approved for clinical use and is intended for laboratory research purposes only. Its mechanism of action involves potent and selective inhibition of Axl and Mer, which blocks downstream signaling pathways and induces apoptosis in cancer cells. This compound is valuable for validating Axl and Mer as therapeutic targets in cancer and for investigating resistance mechanisms to targeted therapies. |
| Molecular Formula |
C32H26N4O6
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|---|---|
| Molecular Weight |
562.5720
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| Exact Mass |
562.185
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| Elemental Analysis |
C, 68.32; H, 4.66; N, 9.96; O, 17.06
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| CAS # |
1646839-59-9
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| Related CAS # |
1646839-59-9
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| PubChem CID |
90645873
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.8
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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 |
7
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| Heavy Atom Count |
42
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| Complexity |
1100
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WHMMKPWGWNYYFE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H26N4O6/c1-40-28-16-21-24(17-29(28)41-2)33-14-13-27(21)42-20-11-12-30(34-18-20)35-31(38)23-15-22-25(9-6-10-26(22)37)36(32(23)39)19-7-4-3-5-8-19/h3-5,7-8,11-18H,6,9-10H2,1-2H3,(H,34,35,38)
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| Chemical Name |
N-[5-(6,7-dimethoxyquinolin-4-yl)oxypyridin-2-yl]-2,5-dioxo-1-phenyl-7,8-dihydro-6H-quinoline-3-carboxamide
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| Synonyms |
tamnorzatinib; ONO-7475; ONO7475; ONO 7475
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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: 100~250 mg/mL (177.8~444.4 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7776 mL | 8.8878 mL | 17.7756 mL | |
| 5 mM | 0.3555 mL | 1.7776 mL | 3.5551 mL | |
| 10 mM | 0.1778 mL | 0.8888 mL | 1.7776 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 |
| NCT03730337 | Completed | Drug: ONO-7475 + ONO-4538 Drug: ONO-7475 |
Advanced or Metastatic Solid Tumors |
Ono Pharmaceutical Co. Ltd | October 17, 2018 | Phase 1 |
| NCT03176277 | Terminated | Drug: ONO-7475 + venetoclax Drug: ONO-7475 |
Myelodysplastic Syndromes Acute Leukemia |
Ono Pharmaceutical Co. Ltd | June 26, 2017 | Phase 1 Phase 2 |
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