AZ-23 (AZ23)
(Synonyms: 5-氯-N-[(1S)-1-(5-氟吡啶-2-基)乙基]-N'-(5-异丙氧基-1H-吡唑-3-基)嘧啶-2,4-二胺,AZ23; AZ 23) 目录号 : GC33090
AZ-23 (AZ23) 是一种 ATP 竞争性和口服生物可利用的 Trk 激酶 A/B/C 抑制剂，IC50 为 2 nM (TrkA)、8 nM (TrkB)、24 nM (FGFR1)、52 nM (Flt3)、55分别为 nM (Ret)、84 nM (MuSk)、99 nM (Lck)。
Cas No.:915720-21-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Exponentially growing TF-1 cells are treated with various concentrations of AZ-23 and then incubated for an additional 72 h at 37°C in either growth or basal medium plus 100 ng/mL NGF. Cell proliferation is measured using MTS solution[1]. |
Animal experiment: | Mice[1] Tumor-bearing mice are given a single, oral dose of compound and individual mice are sacrificed at various time points postdose (2, 6, 16, or 24 hours). Tumors are excised and homogenized and the resulting tumor lysates are analyzed using an ELISA for pTrkA[1]. |
References: [1]. Thress K, et al. Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway. Mol Cancer Ther. 2009 Jul; 8(7):1818-27. | |
AZ-23 is an ATP-competitive and orally bioavailable Trk kinase A/B/C inhibitor with IC50s of 2 nM (TrkA), 8 nM (TrkB), 24 nM (FGFR1), 52 nM (Flt3), 55 nM (Ret), 84 nM (MuSk), 99 nM (Lck), respectively.
AZ-23 potently and selectivity inhibits Trk phosphorylation in cells. AZ-23 potently inhibits Trk-mediated survival (EC50 of 2 nM). AZ-23 Inhibits Trk-Dependent Survival in MCF10ATrkA-δ and TF-1 Cell Lines[1].
AZ-23 shows in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma[1].
[1]. Thress K, et al. Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway. Mol Cancer Ther. 2009 Jul; 8(7):1818-27.
| Cas No. | 915720-21-7 | SDF | |
| 别名 | 5-氯-N-[(1S)-1-(5-氟吡啶-2-基)乙基]-N'-(5-异丙氧基-1H-吡唑-3-基)嘧啶-2,4-二胺,AZ23; AZ 23 | ||
| Canonical SMILES | CC(OC1=CC(NC2=NC(N[C@H](C3=NC=C(F)C=C3)C)=NC=C2Cl)=NN1)C | ||
| 分子式 | C17H19ClFN7O | 分子量 | 391.83 |
| 溶解度 | DMSO : 125 mg/mL (319.02 mM) | 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 | 2.5521 mL | 12.7606 mL | 25.5213 mL |
| 5 mM | 0.5104 mL | 2.5521 mL | 5.1043 mL |
| 10 mM | 0.2552 mL | 1.2761 mL | 2.5521 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。
Blocking Cancer-Nerve Crosstalk for Treatment of Metastatic Bone Cancer Pain
Adv Mater 2022 Apr;34(17):e2108653.PMID:35244228DOI:10.1002/adma.202108653.
The tumor microenvironment is a complex milieu where neurons constitute an important non-neoplastic cell type. From "cancer neuroscience," the crosstalk between tumors and neurons favors the rapid growth of both, making the cancer-nerve interaction a reciprocally beneficial process. Thus, cancer-nerve crosstalk may provide new targets for therapeutic intervention against cancer and cancer-related symptoms. We proposed a nerve-cancer crosstalk blocking strategy for metastatic bone cancer pain treatment, achieved by Mg/Al layered-double-hydroxide nanoshells (Mg/Al-LDH) with AZ-23 loaded inside and alendronate decorated outside. The pain-causing H+ is rapidly eliminated by the LDH, with neurogenesis inhibited by the antagonist AZ-23. As positive feedback, the decreased pain reverses the nerve-to-cancer Ca2+ crosstalk-related cell cycle, dramatically inhibiting tumor growth. All experiments confirm the improved pain threshold and enhanced tumor inhibition. The study may inspire multidisciplinary researchers to focus on cancer-nerve crosstalk for treating cancer and accompanied neuropathic diseases.
Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway
Mol Cancer Ther 2009 Jul;8(7):1818-27.PMID:19509272DOI:10.1158/1535-7163.MCT-09-0036.
Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.
A new ETV6-NTRK3 cell line model reveals MALAT1 as a novel therapeutic target - a short report
Cell Oncol (Dordr) 2018 Feb;41(1):93-101.PMID:29119387DOI:10.1007/s13402-017-0356-2.
Background: Previously, the chromosomal translocation t(12;15)(p13;q25) has been found to recurrently occur in both solid tumors and leukemias. This translocation leads to ETV6-NTRK3 (EN) gene fusions resulting in ectopic expression of the NTRK3 neurotropic tyrosine receptor kinase moiety as well as oligomerization through the donated ETV6-sterile alpha motif domain. As yet, no in vitro cell line model carrying this anomaly is available. Here we genetically characterized the acute promyelocytic leukemia (APL) cell line AP-1060 and, by doing so, revealed the presence of a t(12;15)(p13;q25). Subsequently, we evaluated its suitability as a model for this important clinical entity. Methods: Spectral karyotyping, fluorescence in situ hybridization (FISH), and genomic and transcriptomic microarray-based profiling were used to screen for the presence of EN fusions. qRT-PCR was used for quantitative expression analyses. Responses to AZ-23 (NTRK) and wortmannin (PI3K) inhibitors, as well as to arsenic trioxide (ATO), were assessed using colorimetric assays. An AZ-23 microarray screen was used to define the EN targetome, which was parsed bioinformatically. MAPK1 and MALAT1 activation were assayed using Western blotting and RNA-FISH, respectively, whereas an AML patient cohort was used to assess the clinical occurrence of MALAT1 activation. Results: An EN fusion was detected in AP1060 cells which, accordingly, turned out to be hypersensitive to AZ-23. We also found that AZ-23 can potentiate the effect of ATO and inhibit the phosphorylation of its canonical target MAPK1. The AZ-23 microarray screen highlighted a novel EN target, MALAT1, which also proved sensitive to wortmannin. Finally, we found that MALAT1 was massively up-regulated in a subset of AML patients. Conclusions: From our data we conclude that AP-1060 may serve as a first publicly available preclinical model for EN. In addition, we conclude that these EN-positive cells are sensitive to the NTRK inhibitor AZ-23 and that this inhibitor may potentiate the therapeutic efficacy of ATO. Our data also highlight a novel AML EN target, MALAT1, which was so far only conspicuous in solid tumors.
Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors
ACS Med Chem Lett 2012 Jul 26;3(9):705-9.PMID:24900538DOI:10.1021/ml300074j.
Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.
Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases
J Med Chem 2008 Aug 14;51(15):4672-84.PMID:18646745DOI:10.1021/jm800343j.
The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.