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| Other Sizes |
Purity: =99.44%
| Targets |
EGFRT790M (IC50 = 0.37 nM); EGFRL858R/T790M (IC50 = 0.29 nM); EGFRdel19 T790M (IC50 = 0.21 nM)
Epidermal growth factor receptor (EGFR) - irreversible, third-generation tyrosine kinase inhibitor targeting sensitizing and T790M resistance mutations. |
|---|---|
| ln Vitro |
HS-10296 is a potentially anti-tumor drug that is administered orally and inhibits the EGFR mutant form T790M, which may be used to treat non-small cell lung cancer[2]. Furthermore, HS-10296 may be able to suppress mutations that are sensitive to EGFR, such as G719X, del19, L858R, and L861Q[3].
In vitro enzymatic assays demonstrate that Almonertinib is a potent inhibitor of mutant EGFR with an IC50 of 0.18 nM for EGFRL858R/T790M, while showing selectivity over wild-type EGFR (IC50 = 2.6 nM). The compound is an irreversible, third-generation EGFR tyrosine kinase inhibitor with high selectivity for EGFR-sensitizing and T790M resistance mutations. The T790M mutation is a common resistance mechanism to first-generation EGFR TKIs in NSCLC patients. By irreversibly binding to EGFR, Almonertinib overcomes T790M-mediated resistance and effectively inhibits EGFR signaling in cancer cells. |
| ln Vivo |
The experimental results of nude mice showed that compared with the control group and the positive control ositinib (AZD9291) group, the tumor growth was significantly inhibited, the weight of nude mice, the tumor volume and the tumor mass were significantly reduced in the almonertinib treatment group (all P<0.05)[4].
In vivo studies have demonstrated that Almonertinib shows strong efficacy in preclinical and clinical studies for non-small cell lung cancer, particularly in patients with EGFR mutation-driven tumors. The compound's oral bioavailability and irreversible binding to EGFR support its use as a therapeutic agent for NSCLC. Almonertinib has been evaluated in clinical trials for the treatment of EGFR-mutant NSCLC and has shown promising efficacy in patients with T790M-positive tumors. The compound's selectivity for mutant EGFR over wild-type EGFR may reduce the risk of skin rash and diarrhea, common side effects of first-generation EGFR TKIs. |
| Enzyme Assay |
EGFR kinase activity assays are performed using purified recombinant EGFR proteins (wild-type, L858R/T790M mutant) and a suitable peptide substrate, along with ATP. The enzyme is incubated with the substrate and varying concentrations of Almonertinib, 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 to confirm the compound's specificity for EGFR.
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| Cell Assay |
NSCLC cells H1975 and PC-9 were cultured in vitro. The effects of almonertinib on the proliferation, apoptosis, invasion, and migration of H1975 and PC-9 cells were detected by CCK-8 assay, apoptotic assay and Transwell assay. The expression of invasion and migration related proteins was detected by Western blotting[4].
Cellular assays for Almonertinib typically involve culturing EGFR-mutant NSCLC cell lines (e.g., HCC827, PC-9, H1975) and treating them with the compound at various concentrations. Cell viability is assessed using MTT or CellTiter-Glo assays, and IC50 values are calculated. EGFR 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. Cytotoxicity against normal cells is assessed in parallel to evaluate selectivity. |
| Animal Protocol |
Centrifuge H1975 cells, wash with PBS, and suspend in serum-free RPMI 1640 medium. Then inject 3 × 106 cells per mouse subcutaneously into the right shoulder of 4-6 week old nude mice. After the tumor grows to 100 mm3, it will be randomly divided into three groups, with 5 mice in each group. Each group will be given 0.2 mL of dimethyl sulfoxide, 5 mg/kg AZD9291, and 5 mg/kg of amitinib by gavage, once every two days. Monitor the weight and tumor size of nude mice before each injection. The tumor volume is 2/2 of its length and width, and the entire process lasts for 21 days[4].
In vivo efficacy of Almonertinib is evaluated in mouse xenograft models using EGFR-mutant NSCLC cell lines. Tumor-bearing mice are treated with Almonertinib via oral administration, and tumor volume is monitored over time. Endpoints include tumor growth inhibition, assessment of EGFR 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. Clinical trials have been conducted to evaluate the safety and efficacy of Almonertinib in patients with EGFR-mutant NSCLC. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Almonertinib have been characterized in preclinical and clinical studies. The compound is orally bioavailable and has a molecular weight of 525.64. Key PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are determined using LC-MS/MS analysis of plasma samples following oral administration. The compound's favorable pharmacokinetic profile supports its use as a once-daily oral therapy. Almonertinib is metabolized primarily by CYP3A4, and its metabolites are excreted in urine and feces. Toxicological evaluation of Almonertinib has been conducted in preclinical and clinical studies to support its clinical development. Standard toxicology assessments include acute and repeated-dose toxicity studies in rodents and non-rodent species, genotoxicity assays, and reproductive and developmental toxicity studies. Common side effects of EGFR TKIs include skin rash, diarrhea, and stomatitis. Almonertinib's selectivity for mutant EGFR over wild-type EGFR may reduce the incidence of skin rash and diarrhea compared to first-generation TKIs.
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| References |
[4]. Effect of almonertinib on the proliferation, invasion, and migration in non-small cell lung cancer cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban . 2021 Oct 28;46(10):1045-1053. doi: 10.11817/j.issn.1672-7347.2021.201009.
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| Additional Infomation |
Almonertinib is a third-generation EGFR tyrosine kinase inhibitor that targets EGFR-sensitive mutations and T790M resistance mutations. Its efficacy in treating advanced or metastatic EGFR-mutant non-small cell lung cancer (NSCLC) is currently being investigated. Oumolertinib is an oral epidermal growth factor receptor (EGFR) T790M mutant inhibitor with potential antitumor activity. After administration, oumolertinib binds to and inhibits EGFR T790M (a secondary resistance mutation), suppressing its tyrosine kinase activity, blocking EGFR T790M-mediated signal transduction, and ultimately leading to the death of EGFR T790M-expressing tumor cells. EGFR is a receptor tyrosine kinase that mutates in various tumor cell types and plays a crucial role in tumor cell proliferation and tumor angiogenesis.
Drug Indications Treatment of Lung CancerMechanism of Action Almonertinib inhibits EGFR tyrosine kinase, targeting EGFR-sensitive mutations and T790M resistance mutations. ...Drug IndicationsAlmonertinib (HS-10296) is an orally available, irreversible, third-generation EGFR tyrosine kinase inhibitor developed for the treatment of non-small cell lung cancer, particularly in patients with EGFR mutation-driven tumors. The compound shows high selectivity for EGFR-sensitizing and T790M resistance mutations, with IC50s of 0.18 nM for EGFRL858R/T790M and 2.6 nM for wild-type EGFR. Almonertinib has shown strong efficacy in preclinical and clinical studies for NSCLC. Its mechanism of action involves irreversible binding to EGFR, which overcomes T790M-mediated resistance and effectively inhibits EGFR signaling in cancer cells. Almonertinib is approved for clinical use in some countries for the treatment of EGFR-mutant NSCLC. |
| Molecular Formula |
C30H35N7O2
|
|---|---|
| Molecular Weight |
525.6446
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| Exact Mass |
525.285
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| Elemental Analysis |
C, 68.55 H, 6.71 N, 18.65 O, 6.09
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| CAS # |
1899921-05-1
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| Related CAS # |
Almonertinib mesylate;2134096-06-1;Almonertinib hydrochloride;2134096-03-8; 1899921-05-1; 2134096-04-9 (sulfate); 2134096-07-2 (fumarate); 2134096-08-3
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| PubChem CID |
121280087
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
39
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| Complexity |
823
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DOEOECWDNSEFDN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H35N7O2/c1-6-29(38)32-24-17-25(28(39-5)18-27(24)36(4)16-15-35(2)3)34-30-31-14-13-23(33-30)22-19-37(20-11-12-20)26-10-8-7-9-21(22)26/h6-10,13-14,17-20H,1,11-12,15-16H2,2-5H3,(H,32,38)(H,31,33,34)
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| Chemical Name |
N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide
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| Synonyms |
Almonertinib; Ameile; HS-10296; HS 10296; HS10296; HS-10296; Aumolertinib; Ameile; HS-10297; Egfr T790M inhibitor HS-10296; Aumolertinib [USAN]; Aumolertinib
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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 (~190.2 mM)
Ethanol: ~6 mg/mL (~11.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (11.89 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 62.5 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: ≥ 6.25 mg/mL (11.89 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 62.5 mg/mL clear DMSO stock solution to 900 μL 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 | 1.9024 mL | 9.5122 mL | 19.0244 mL | |
| 5 mM | 0.3805 mL | 1.9024 mL | 3.8049 mL | |
| 10 mM | 0.1902 mL | 0.9512 mL | 1.9024 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 |
| NCT04687241 | Active Recruiting |
Drug: Placebo Almonertinib Drug: Almonertinib |
Non-small Cell Lung Cancer | Jiangsu Hansoh Pharmaceutical Co., Ltd. |
April 30, 2021 | Phase 3 |
| NCT05826483 | Recruiting | Drug: Almonertinib | Malignant Tumor of Lung Poor Performance Status |
Guangzhou Institute of Respiratory Disease |
January 1, 2022 | Phase 1 |
| NCT04841811 | Recruiting | Drug: Almonertinib | Lung Cancer | Guangdong Association of Clinical Trials |
June 20, 2022 | Phase 3 |
| NCT04882345 | Not yet recruiting | Drug: Almonertinib | EGFR Gene Mutation Lung Cancer |
Shanghai Chest Hospital | July 15, 2021 | Phase 2 |
| NCT04870190 | Not yet recruiting | Drug: Almonertinib Drug: Osimertinib |
NSCLC | Shanghai Chest Hospital | June 1, 2021 | Phase 3 |
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