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Naquotinib (ASP 8273; ASP-8273; ASP8273) is an irreversible/covalent and 3rd-generation inhibitor of epidermal growth factor receptor (EGFR) with potential antitumor activity. It inhibits EGFR with an IC50 of 70 nM.
| Targets |
EGFR (IC50 = 230 nM); EGFRT790M; EGFRL858R/T790M; EGFRL858R; EGFRExon 19 deletion/T790M
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|---|---|
| ln Vitro |
Naquotinib inhibits the growth of PC-9(del ex19), HCC827(del ex19), NCI-H1975(del ex19/T790M), and PC-9ER(del ex19/T790M) with IC50s ranging from 8 to 33 nM in assays utilizing endogenously EGFR-dependent cells[1]. Naquotinib only exhibits inhibitory effects at 1000 nM in A431, but it selectively inhibits the phosphorylation of EGFR and its downstream signal pathway, ERK and Akt, starting at 10 nM in HCC827 and NCI-H1975. While other EGFR-TKIs are only partially effective, Naquotinib inhibits cell growth in NCI-H1650 (del ex19) with an IC50 value of 70nM[2].
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| ln Vivo |
NCI-H1975 (L858R/T790M), HCC827 (del ex19), and PC-9 (del ex19) xenograft models show dose-dependent tumor regression upon oral Naquotinib treatment. Naquotinib is effective regardless of dosage schedules. Two weeks of treatment with Naquotinib results in complete tumor regression in an NCI-H1975 xenograft model. Over 85 days following the end of Naquotinib treatment, 50% of mice continue to exhibit complete regression[2].
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| References | |
| Additional Infomation |
Naquotinib has been used in trials studying the treatment of Solid Tumors, Non-small Cell Lung Cancer, Non-Small-Cell Lung Cancer (NSCLC), Epidermal Growth Factor Receptor Mutations, and Epidermal Growth Factor Receptor (EGFR) Mutations, among others.
Naquotinib is an orally available, irreversible, third-generation, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, ASP8273 covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. ASP8273 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced as compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR. |
| Molecular Formula |
C30H42N8O3
|
|---|---|
| Molecular Weight |
562.719
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| Exact Mass |
562.338
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| Elemental Analysis |
C, 64.03; H, 7.52; N, 19.91; O, 8.53
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| CAS # |
1448232-80-1
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| Related CAS # |
Naquotinib mesylate;1448237-05-5
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| PubChem CID |
71667668
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
717.6±60.0 °C at 760 mmHg
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| Flash Point |
387.8±32.9 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.624
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| LogP |
3.74
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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 |
9
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| Heavy Atom Count |
41
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| Complexity |
883
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| Defined Atom Stereocenter Count |
1
|
| SMILES |
O(C1=C(C([H])([H])C([H])([H])[H])N=C(C(N([H])[H])=O)C(=N1)N([H])C1C([H])=C([H])C(=C([H])C=1[H])N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])[C@@]1([H])C([H])([H])N(C(C([H])=C([H])[H])=O)C([H])([H])C1([H])[H]
|
| InChi Key |
QKDCLUARMDUUKN-XMMPIXPASA-N
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| InChi Code |
InChI=1S/C30H42N8O3/c1-4-25-30(41-24-12-15-38(20-24)26(39)5-2)34-29(27(33-25)28(31)40)32-21-6-8-22(9-7-21)36-13-10-23(11-14-36)37-18-16-35(3)17-19-37/h5-9,23-24H,2,4,10-20H2,1,3H3,(H2,31,40)(H,32,34)/t24-/m1/s1
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| Chemical Name |
6-ethyl-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrazine-2-carboxamide
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| Synonyms |
Naquotinib free base; ASP-8273; ASP8273; ASP 8273
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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) |
Ethanol: ~100 mg/mL (~177.7 mM)
DMSO: ~52 mg/mL (~92.4 mM) |
|---|---|
| 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 | 1.7771 mL | 8.8854 mL | 17.7708 mL | |
| 5 mM | 0.3554 mL | 1.7771 mL | 3.5542 mL | |
| 10 mM | 0.1777 mL | 0.8885 mL | 1.7771 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 |
| NCT02588261 | Terminated | Drug: naquotinib mesilate Drug: Erlotinib |
Non-small Cell Lung Cancer (NSCLC) |
Astellas Pharma Global Development, Inc. |
February 11, 2016 | Phase 3 |
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