EAI001
目录号 : GC66432
EAI001 是一个有效的选择性突变体表皮生长因子受体 (EGFR) 变构抑制剂，抑制 EGFRL858R/T790M 的 IC50 值为 24 nM。EAI001 可用于癌症研究。
Cas No.:892772-75-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
EAI001 is a potent, selective mutant epidermal growth factor receptor (EGFR) allosteric inhibitor with an IC50 value of 24 nM for EGFRL858R/T790M. EAI001 can be used for research of cancer[1][2].
EAI001 (50 μM) binds to EGFR T790M/C797S/V948R that lies deep inside the EGFR towards the ATP binding site and C-helix. EAI001 showed inhibitory activity due to hydrophobic interaction with amino acid Ile759, Leu747, Leu788, Leu777 and Met766[1].
| Cas No. | 892772-75-7 | SDF | Download SDF |
| 分子式 | C19H15N3O2S | 分子量 | 349.41 |
| 溶解度 | 储存条件 | 4°C, away from moisture and light | |
| 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 | 2.862 mL | 14.3098 mL | 28.6197 mL |
| 5 mM | 0.5724 mL | 2.862 mL | 5.7239 mL |
| 10 mM | 0.2862 mL | 1.431 mL | 2.862 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 | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance
Pharmacol Rep 2020 Aug;72(4):799-813.PMID:32666476DOI:10.1007/s43440-020-00131-0.
Background: The epidermal growth factor receptor (EGFR) inhibitors represent the first-line therapy regimen for non-small cell lung cancer (NSCLC). Most of these inhibitors target the ATP-site to stop the aggressive development of NSCLC. Stabilization of the ATP-binding on EGFR is difficult due to autophosphorylation of the EGFR domain. This leads to activation of nonintrinsic influence of the tumor microenvironment and expression of anti-apoptotic pathways and drug resistance. Methods: The NSCLC related literature search was carried out using online databases such as Scopus, Web of Sciences, PubMed, Protein Data Bank and UniPort for the last ten years and selected articles are referred for discussion in this review. Results: To overcome the problem of mutations in NSCLC, the allosteric site of EGFR was targeted, which shows significant therapeutic outcome without causing resistance. Compounds like EAI001, EAI045 JBJ-04-125-02, DDC4002 and a series of small molecules with an affinity towards the EGFR allosteric site are reported and are under the investigational stage. These compounds are categorized under fourth-generation anti-NSCLC agents. Conclusion: Composition of this review highlights the advantage of inhibiting allosteric site in the EGFRTK receptor domains and presents a comparative analysis of the new fourth-generation anti-NSCLC agents to overcome the drug resistance.
Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045
Biochem Biophys Res Commun 2018 Jul 20;502(3):332-337.PMID:29802850DOI:10.1016/j.bbrc.2018.05.154.
Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding. Therefore to develop new TKIs to overcome EGFR drug-resistant mutants harboring T790M/C797S is urgently demanded. EAI001 and EAI045 are a new type of EGFR TKIs that bind to EGFR reversibly and not relying on Cys 797. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR L858R/T790M and L858R/T790M/C797S. Here we report the crystal structure of EGFR T790M/C797S/V948R in complex with EAI045, and compare it to EGFR T790M/V948R in complex with EAI001. The complex structure reveals why EAI045 binds tighter to EGFR than does EAI001, and why EAI001 and EAI045 prefer binding to EGFR T790M. The knowledge may facilitate future drug development studies targeting this very important cancer target.
Insight into binding mechanisms of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations
J Biomol Struct Dyn 2019 Oct;37(16):4384-4394.PMID:30499387DOI:10.1080/07391102.2018.1552197.
Lung cancer is the leading cause of cancer death, and epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding. Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In this study, molecular dynamics simulations and free energy calculations were carried out on EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.