AZD-9291
(Synonyms: 奥希替尼; AZD-9291; Mereletinib) 目录号 : GC16308
An inhibitor of mutant EGFR
Cas No.:1421373-65-0
Sample solution is provided at 25 µL, 10mM.
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AZD-9291 is an irreversible inhibitor of mutant EGFR kinase with IC50 values of 15nM, 17nM and 480nM, respectively for L858R/T790M, ex19del and wild-type EGFR [1].
A series of mutations cause the resistance of EGFR, AZD-9291 is developed for an irreversible and selective inhibitor of the mutant EGFR. AZD-9291 binds to the ATP binding site of EGFR by targeting Cys 797. In EGFR recombinant enzyme assay, AZD-9291 shows about 200 times greater potency against the mutant EGFR than wild-type EGFR. AZD-9291 does not exhibit significant activity towards other receptor kinase. In vitro assays show that AZD-9291can inhibit EGFR phosphorylation with lower IC50 value in cell lines harboring sensitising EGFR mutants than in wild-type cell lines. Additionally, AZD9291 can induce profound shrinkage in mutant EGFR at low doses in xenograft models. This also happens in transgenic mouse tumor models. Mice treated with AZD9291 at the dose of 5 mg/kg/day display 80% reduction in tumor volume [1].
AZD-9291是一种不可逆的突变型EGFR激酶选择性抑制剂，对L858R/T790M、ex19del和野生型EGFR的IC50值分别为15nM、17nM和480nM [1]。
一系列的突变导致EGFR耐药，AZD-9291是为突变EGFR开发的一种不可逆选择性抑制剂。AZD-9291通过靶向Cys 797来结合EGFR的ATP结合位点。在EGFR重组酶测定中，AZD-9291对突变型EGFR的亲和力比野生型EGFR高出约200倍。AZD-9291对其他受体酶的活性影响不显著。体外实验表明，AZD-9291可以抑制细胞系中的EGFR磷酸化，突变型EGFR的抑制效果比野生型细胞系更强。此外，AZD-9291可以在低剂量下诱导突变型EGFR在异种移植瘤模型中显著萎缩。这也出现在转基因小鼠肿瘤模型中。接受5mg/kg/天AZD9291治疗的小鼠肿瘤体积减少了80% [1]。
References:
[1] Darren A. E. Cross, Susan E Ashton, Serban Ghiorghiu, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discovery. 2014, June.
| Cell experiment[1]: | |
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Cell lines |
Human lung cancer cells with EGFR-mutations or wild type EGFR stable expression |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Applications |
AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; < 25 nM) and EGFR m+/T790M (e.g. H1975; < 25 nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; > 500 nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. |
| Animal experiment[1]: | |
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Animal models |
EGFRm+ and EGFRm+/T790M transgenic mice |
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Dosage form |
5 mg/kg |
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Applications |
AZD9291 administered once daily orally at 5 mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5 mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: 1. Darren Cross1, Sue Ashton1, Caroline Nebhan2 et al. AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma. Mol Cancer Ther 2013;12(11 Suppl):A109. |
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| Cas No. | 1421373-65-0 | SDF | |
| 别名 | 奥希替尼; AZD-9291; Mereletinib | ||
| Canonical SMILES | CN1C=C(C2=NC(NC3=C(OC)C=C(N(CCN(C)C)C)C(NC(C=C)=O)=C3)=NC=C2)C4=C1C=CC=C4 | ||
| 分子式 | C28H33N7O2 | 分子量 | 499.61 |
| 溶解度 | ≥ 24.98mg/mL in DMSO | 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 | 2.0016 mL | 10.0078 mL | 20.0156 mL |
| 5 mM | 0.4003 mL | 2.0016 mL | 4.0031 mL |
| 10 mM | 0.2002 mL | 1.0008 mL | 2.0016 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。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet