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ONO-7475 is a novel and orally bioactive dual Axl/Mer inhibitor with anticancer activity by targeting both Axl and Mer, and preventing their activity. This prevents tumor cells that overexpress Axl and Mer from proliferating and migrating by blocking the signal transduction pathways mediated by these proteins. Numerous tumor cell types overexpress Axl and Mer, two RTKs belonging to the TAM (Tyro3, Axl, and Mer) family. Their expression is linked to poor prognosis and drug resistance. They are important in the growth, survival, invasion, angiogenesis, and metastasis of tumor cells.
| Targets |
Axl (IC50 = 0.7 nM); Mer (IC50 = 1 nM); FLT3 (IC50 = 147 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]
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| 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]
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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.
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| Animal Protocol |
4-week old female NSG mice bearing MOLM13 cells
6 mg/kg, 20 mg/kg Oral gavage |
| References | |
| Additional Infomation |
Tamnorzatinib is an orally available and selective inhibitor of the receptor tyrosine kinases (RTKs) Axl (UFO) and Mer, with potential antineoplastic activity. Upon administration, tamnorzatinib targets and binds to both Axl and Mer, and prevents their activity. This blocks Axl- and Mer-mediated signal transduction pathways, and inhibits proliferation and migration of Axl- and Mer-overexpressing tumor cells. Axl and Mer, both members of the TAM (Tyro3, Axl and Mer) family of RTKs, are overexpressed by many tumor cell types. They play key roles in tumor cell proliferation, survival, invasion, angiogenesis and metastasis, and their expression is associated with drug resistance and poor prognosis.
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| 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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