Avitinib
(Synonyms: 艾维替尼,Abivertinib; AC0010) 目录号 : GC42884
A selective inhibitor of mutant EGFR
Cas No.:1557267-42-1
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.00%
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Avitinib is a pyrrolopyrimidine-based, irreversible inhibitor of the epidermal growth factor receptor (EGFR). It is selective for EGFR-active and T790M mutations, exhibiting a 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of 500 mg/kg avitinib was shown to result in complete remission of tumors with EGFR-active and T790M mutations.
| Cas No. | 1557267-42-1 | SDF | |
| 别名 | 艾维替尼,Abivertinib; AC0010 | ||
| Canonical SMILES | CN1CCN(C2=C(F)C=C(NC3=NC(OC4=CC(NC(C=C)=O)=CC=C4)=C(C=CN5)C5=N3)C=C2)CC1 | ||
| 分子式 | C26H26FN7O2 | 分子量 | 487.5 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 30 mg/ml,Ethanol:PBS (pH 7.2) (1:10): 0.9 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0513 mL | 10.2564 mL | 20.5128 mL |
| 5 mM | 0.4103 mL | 2.0513 mL | 4.1026 mL |
| 10 mM | 0.2051 mL | 1.0256 mL | 2.0513 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Effects of Avitinib on the pharmacokinetics of osimertinib in vitro and in vivo in rats
Thorac Cancer 2020 Oct;11(10):2775-2781.PMID:32812378DOI:10.1111/1759-7714.13587.
Background: Avitinib is one type of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of Avitinib on the pharmacokinetics of osimertinib, one FDA approved third-generation TIKI, both in vitro and in vivo. Methods: The in vitro metabolic stability and inhibitory effect of Avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC50 values. For the in vivo study, 18 Sprague-Dawley rats were randomly divided into three groups: the Avitinib multiple dose group (30 mg/kg Avitinib once daily for seven days), the Avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg Avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS-MS was used for the determination of the concentration of osimertinib in plasma. Results: In vitro analysis revealed that the IC50 value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with Avitinib, the values of AUC and MRT of the osimertinib were increased, and its Cmax and Tmax were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05). Conclusions: Both in vitro and in vivo results demonstrated that a drug-drug interaction between Avitinib and osimertinib occurred and more attention should be paid when Avitinib and osimertinib are synchronously administered in clinic. Key points: SIGNIFICANT FINDINGS OF THE STUDY: Osimertinib is the only market available third-generation EGFR-TKI and it has been reported that some drugs could have drug-drug interactions with it. What this study adds: For the first time, we systematically investigated the effect of Avitinib, one newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model.
Effects of Avitinib on CYP450 Enzyme Activity in vitro and in vivo in Rats
Drug Des Devel Ther 2021 Aug 21;15:3661-3673.PMID:34456561DOI:10.2147/DDDT.S323186.
Purpose: Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of Avitinib on cytochrome CYP450 enzymes metabolic activity. Methods: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg Avitinib once daily for 7 days (Avitinib multiple-doses group), 30 mg/kg Avitinib on day 7 (Avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC50 values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program. Results: In vitro experiments revealed different inhibitory effects of Avitinib on the six probe substrates with various IC50 values (bupropion, 6.39/22.64 μM; phenacetin, 15.79/48.36 μM; chlorzoxazone, 23.15/57.09 μM; midazolam, 27.64/59.6 μM; tolbutamide, 42.18/6.91 μM; dextromethorphan, 44.39/56.57 μM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences (P <0.05) in distinct pharmacokinetic parameters (AUC(0-t), AUC (0-∞), Cmax, MRT(0-t), MRT (0-∞), and CLz/F) for the six probe substrates after Avitinib pretreatment. Conclusion: A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when Avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.
Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers
Pharmacol Res 2019 Jan;139:395-411.PMID:30500458DOI:10.1016/j.phrs.2018.11.014.
The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ErbB3 is kinase impaired. Surprisingly, the ErbB2-ErbB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (746ELREA750) or the exon-21 L858R substitution. Gefitinib and erlotinib are orally effective type I reversible EGFR mutant inhibitors; type I inhibitors bind to an active enzyme conformation. Unfortunately, secondary resistance to these drugs occurs within about one year owing to a T790M gatekeeper mutation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein. Resistance also develops to this and related type VI inhibitory drugs owing to a C797S mutation; the serine residue is unable to react with the drugs to form a covalent bond. Approximately 20% of breast cancer patients exhibit ErbB2/HER2 gene amplification on chromosome 17q. One of the earliest targeted treatments in cancer involved the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain ErbB2/HER2 causing its down regulation. Surgery, radiation therapy, chemotherapy with cytotoxic drugs, and hormonal modulation are the mainstays in the treatment of breast cancer. Moreover, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used in the treatment of selected breast cancer patients. Of the approximate three dozen FDA-approved small molecule protein kinase inhibitors, five are type VI irreversible inhibitors and four of them including afatinib, osimertinib, dacomitinib, and neratinib are directed against the ErbB family of receptors (ibrutinib is the fifth and it targets Bruton tyrosine kinase). Avitinib, olmutinib, and pelitinib are additional type VI inhibitors in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the norm, and devising and implementing strategies for minimizing or overcoming resistance is an important goal in cancer therapeutics.
Antifibrotic mechanism of Avitinib in bleomycin-induced pulmonary fibrosis in mice
BMC Pulm Med 2023 Mar 22;23(1):94.PMID:36949426DOI:10.1186/s12890-023-02385-9.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of Avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of Avitinib in pulmonary fibrosis. In vivo experiments first verified that Avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that Avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-β1/Smad3 signalling pathways. The cellular experiments also indicated that Avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that Avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.
Reactive intermediates and bioactivation pathways characterization of Avitinib by LC-MS/MS: In vitro metabolic investigation
J Pharm Biomed Anal 2019 Feb 5;164:659-667.PMID:30472584DOI:10.1016/j.jpba.2018.11.033.
Avitinib (AC0010) is a third generation inhibitor of the EGFR (epidermal growth factor receptor) that was permitted parallel phase I clinical trials in the US and in 2014. It is estimated to enter in market within two years. In the current study, eight in vitro metabolites were detected and their chemical structures were postulated. The main in vitro phase-I metabolic reaction was N-oxidation in piperazine moiety. The generation of reactive metabolites in Avitinib metabolism was investigated using rat liver microsomes while adding capturing agents, viz potassium cyanide for reactive iminium intermediates, GSH for iminoquinones and methoxylamine for aldehyde forming stable adducts which are identifiable by LC-MS/MS. Ten reactive intermediates (four iminoquinones, three iminium and three aldehydes) were characterized. The three capturing agents used resulted in proposing four different bioactivation pathways. Upon literature examination, no former articles were found for Avitinib metabolism including the produced reactive metabolites.