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| Targets |
Naquotinib mesylate targets the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is frequently mutated in non-small cell lung cancer (NSCLC). The compound is a third-generation, irreversible EGFR TKI that selectively targets EGFR mutations, including the T790M resistance mutation. By irreversibly binding to EGFR, Naquotinib prevents EGFR-mediated signaling, inhibiting tumor cell proliferation and survival. The compound's selectivity for mutant EGFR over wild-type EGFR may reduce the skin rash and gastrointestinal toxicity associated with first-generation EGFR TKIs. Naquotinib is an investigational drug for the treatment of NSCLC.
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| ln Vitro |
Naquotinib decreased the expression of PC-9(del ex19), HCC827(del ex19), NCI-H1975(del ex19/T790M), and PC-9ER(del ex19/T790M) in experiments utilizing endogenous EGFR-dependent cells. Growth, 8–33 nM is the IC50[1]. While the inhibitory impact of naquotinib was only observed at 1000nM in A431, it specifically decreased the phosphorylation of EGFR and its downstream signaling pathways, ERK and Akt, in HCC827 and NCI-H1975, commencing at 10nM. While other EGFR-TKIs were only partially successful, Naquotinib suppressed cell proliferation in NCI-H1650 (del ex19) with an IC50 value of 70nM [2].
In vitro, Naquotinib mesylate inhibits the growth of NSCLC cells with EGFR activating and T790M resistance mutations. The compound has an IC₅₀ of 70 nM for NCI-H1650 cell growth. In cell-based assays, Naquotinib treatment results in inhibition of EGFR phosphorylation and downstream signaling pathways, leading to reduced cell proliferation and increased apoptosis. The compound is selective for mutant EGFR over wild-type EGFR. Naquotinib's in vitro activity has been characterized in a panel of NSCLC cell lines with various EGFR mutations. These findings support the compound's potential as a targeted therapy for EGFR-mutant NSCLC. |
| ln Vivo |
Tumor regression was dose-dependently promoted in NCI-H1975 (L858R/T790M), HCC827 (del ex19), and PC-9 (del ex19) xenograft models by oral nargotinib treatment. The effectiveness of narcotinib remains unaffected by the dose schedule. After 14 days of nalcutinib treatment, tumor regression was fully achieved in the NCI-H1975 xenograft model. More than 85 days after nalcutinib medication was stopped, 50% of the mice continued to exhibit complete regression [2].
In vivo, Naquotinib mesylate has been evaluated in preclinical models and clinical trials for the treatment of NSCLC. The compound is orally bioavailable and has demonstrated antitumor activity in mouse xenograft models of EGFR-mutant NSCLC. In clinical studies, Naquotinib has been investigated as a potential treatment for patients with EGFR-mutant NSCLC, including those with the T790M resistance mutation. The compound's oral bioavailability and favorable pharmacokinetic profile support its use as an investigational therapeutic agent. Specific clinical efficacy data are available from clinical trial publications. |
| Enzyme Assay |
In vitro enzyme assays for Naquotinib mesylate typically involve measuring the inhibition of EGFR kinase activity. A typical protocol: recombinant EGFR (wild-type or mutant) is incubated with varying concentrations of Naquotinib (0.01 nM to 10 μM) in kinase assay buffer (50 mM HEPES, pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35) for 30 minutes at room temperature. ATP (10 μM) and a peptide substrate are added, and the reaction is incubated for 60 minutes. Phosphorylated substrate is detected by time-resolved fluorescence resonance energy transfer (TR-FRET) or by scintillation proximity assay (SPA). IC₅₀ values are calculated from inhibition curves. Positive controls include osimertinib or afatinib. Each concentration is tested in triplicate, and experiments are repeated at least three times.
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| Cell Assay |
In vitro cell-based assays for Naquotinib mesylate are performed using NSCLC cell lines such as NCI-H1650, NCI-H1975 (T790M), or PC-9. A typical protocol: cells are seeded in 96-well plates at 5,000-10,000 cells/well and allowed to adhere overnight. Cells are treated with Naquotinib at concentrations ranging from 0.1 nM to 10 μM for 48-72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. EGFR phosphorylation is measured by Western blot or ELISA using anti-phospho-EGFR antibodies. Downstream signaling (p-ERK, p-AKT) is assessed by Western blot. Cell cycle and apoptosis are analyzed by flow cytometry. Each condition is tested in triplicate, and experiments are repeated at least three times.
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| Animal Protocol |
In vivo animal studies for Naquotinib mesylate are conducted in mouse xenograft models of EGFR-mutant NSCLC. A typical protocol: immunocompromised mice are inoculated subcutaneously with NSCLC cells (e.g., NCI-H1975 or PC-9). When tumors reach 50-100 mm³, mice are randomized to receive Naquotinib via oral gavage at doses of 1-30 mg/kg, daily, for 2-4 weeks. Tumor volumes are measured with calipers every 2-3 days, and body weight is monitored for toxicity. At study termination, tumors are harvested for histopathological examination and biomarker analysis (e.g., EGFR phosphorylation by IHC or Western blot). Efficacy is assessed by comparing tumor growth between treatment and vehicle control groups.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Naquotinib mesylate have been characterized in preclinical and clinical studies. The compound is orally bioavailable. Following oral administration, Naquotinib is absorbed and reaches therapeutic concentrations in the systemic circulation. Its half-life, volume of distribution, clearance, and protein binding have been evaluated in preclinical models and in clinical trials. The compound is metabolized in the liver, and its metabolites are eliminated via the renal and biliary routes. The compound's pharmacokinetic profile supports once-daily dosing in clinical studies. Specific pharmacokinetic parameters have been reported in clinical trial publications.
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| Toxicity/Toxicokinetics |
Toxicological data for Naquotinib mesylate have been evaluated in preclinical and clinical studies. The compound is generally well-tolerated at therapeutic doses. Common adverse effects may include diarrhea, skin rash (less than with first-generation EGFR TKIs), and gastrointestinal disturbances. The compound has not been associated with significant organ toxicity in preclinical studies. Standard laboratory safety precautions should be followed when handling Naquotinib mesylate: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored as recommended by the manufacturer. Researchers should consult the safety data sheet (SDS) before handling.
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| References |
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| Additional Infomation |
Additional information for Naquotinib mesylate: The compound has a CAS number of 1448237-05-5. Its molecular formula is C₃₁H₄₆N₈O₆S and molecular weight is 658.81 g/mol. Synonyms include ASP8273. It is an orally bioavailable, third-generation, irreversible EGFR tyrosine kinase inhibitor. It selectively targets EGFR mutations, including T790M. IC₅₀ = 70 nM for NCI-H1650 cell growth. It is an investigational drug for NSCLC. It is for research use only and is not approved for clinical applications outside of investigational studies. No FDA approvals exist.
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| Molecular Formula |
C31H46N8O6S
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| Molecular Weight |
658.811945438385
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| Exact Mass |
658.326
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| CAS # |
1448237-05-5
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| Related CAS # |
Naquotinib;1448232-80-1
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| PubChem CID |
92135932
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
46
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| Complexity |
976
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)O[C@@H]5CCN(C5)C(=O)C=C.CS(=O)(=O)O
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| InChi Key |
ALDUQYYVQWGTMR-GJFSDDNBSA-N
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| InChi Code |
InChI=1S/C30H42N8O3.CH4O3S/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;1-5(2,3)4/h5-9,23-24H,2,4,10-20H2,1,3H3,(H2,31,40)(H,32,34);1H3,(H,2,3,4)/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;methanesulfonic acid
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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 : ~12.5 mg/mL (~18.97 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.04 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 20.0 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 mg/mL (3.04 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline 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 | 1.5179 mL | 7.5894 mL | 15.1789 mL | |
| 5 mM | 0.3036 mL | 1.5179 mL | 3.0358 mL | |
| 10 mM | 0.1518 mL | 0.7589 mL | 1.5179 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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