Tarloxotinib bromide (TH-4000)
(Synonyms: TH-4000) 目录号 : GC32100
Tarloxotinib bromide (TH-4000)是一种不可逆的EGFR/HER2抑制剂前体。
Cas No.:1636180-98-7
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
Tarloxotinib bromide (TH-4000) is an irreversible inhibitor prodrug of EGFR/HER2. In the hypoxic microenvironment of breast tumors (< 0.1% O2), Tarloxotinib bromide is converted into TH-4000E. TH-4000E inhibits the phosphorylation of HER2 dimers and downstream pathways, inducing apoptosis in HER2-positive breast cancer cells through a ROS-dependent mechanism[1-4].
Tarloxotinib bromide (0-10μM; 2h) inhibited pEGFR with IC50 of 201 nM in A431 cell. This suggests that tarloxotinib is much less effective against EGFR, HER2 and HER4 in cells to avoid generating any targeting activity in non-tumor tissues[1].
Tarloxotinib bromide(50 mg/kg, in 20% m/v 2-hydroxypropyl-b-cyclodextrin; i.p; once a week for 21 day) inhibits the growth of HCC-1954 tumors in mice and demonstrates greater efficacy than lapatinib in trastuzumab-resistant breast tumors. Tarloxotinib bromide also reduces the Ki67-positive zone, indicating decreased cell proliferation[2].
References:
[1]. Estrada-Bernal A, Le AT, et,al. Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes. Clin Cancer Res. 2021 Mar 1;27(5):1463-1475. doi: 10.1158/1078-0432.CCR-20-3555. Epub 2020 Dec 22. PMID: 33355298; PMCID: PMC7926264.
[2]. Shao X, Yang D, et,al. TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer. Arch Toxicol. 2024 Mar;98(3):865-881. doi: 10.1007/s00204-023-03670-6. Epub 2024 Jan 11. PMID: 38212449.
[3]. Maddox AL, Brehove MS, et,al. Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer. Cancers (Basel). 2022 Jun 4;14(11):2795. doi: 10.3390/cancers14112795. PMID: 35681773; PMCID: PMC9179327
[4].Phillips RM. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother Pharmacol. 2016 Mar;77(3):441-57. doi: 10.1007/s00280-015-2920-7. Epub 2016 Jan 25. PMID: 26811177; PMCID: PMC4767869.
Tarloxotinib bromide (TH-4000)是一种不可逆的EGFR/HER2抑制剂前体。在乳腺肿瘤缺氧微环境下(O2 < 0.1%)， Tarloxotinib bromide转化为TH-4000E。TH-4000E抑制HER2二聚体磷酸化及其下游通路，通过ROS依赖机制诱导HER2阳性乳腺癌细胞凋亡[1-4]。
Tarloxotinib bromide (0-10μM; 2h)抑制A431细胞pEGFR, IC50为201 nM。这表明Tarloxotinib bromide对细胞中的EGFR、HER2和HER4的有效性要低得多，以避免在非肿瘤组织中产生任何靶向活性[1]。
Tarloxotinib bromide (50 mg/kg, in 20% m/v 2-hydroxypropyl-b-cyclodextrin; i.p; once a week for 21 day)抑制小鼠HCC-1954肿瘤的生长。Tarloxotinib bromide治疗trastuzumab耐药乳腺肿瘤比lapatinib更有效。Tarloxotinib bromide降低了Ki67(marker of cell proliferation)阳性区[2]。
| Cas No. | 1636180-98-7 | SDF | |
| 别名 | TH-4000 | ||
| Canonical SMILES | BrC1=C(Cl)C=CC(NC2=NC=NC3=C2C=C(NC(/C=C/C[N+](C)(C)CC4=C([N+]([O-])=O)N=CN4C)=O)N=C3)=C1.[Br-] | ||
| 分子式 | C24H24Br2ClN9O3 | 分子量 | 681.77 |
| 溶解度 | DMSO : ≥ 33 mg/mL (48.40 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 | 1.4668 mL | 7.3339 mL | 14.6677 mL |
| 5 mM | 0.2934 mL | 1.4668 mL | 2.9335 mL |
| 10 mM | 0.1467 mL | 0.7334 mL | 1.4668 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。
Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome
J Natl Cancer Inst 2018 Jan 1;110(1).PMID:28922791DOI:10.1093/jnci/djx160.
Oxygen deprivation (hypoxia) in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance and poor survival. Hypoxia is an attractive therapeutic target, particularly in the context of radiotherapy, which is delivered to more than half of NSCLC patients. However, NSCLC hypoxia-targeted therapy trials have not yet translated into patient benefit. Recently, early termination of promising evofosfamide and Tarloxotinib bromide studies due to futility highlighted the need for a paradigm shift in our approach to avoid disappointments in future trials. Radiotherapy dose painting strategies based on hypoxia imaging require careful refinement prior to clinical investigation. This review will summarize the role of hypoxia, highlight the potential of hypoxia as a therapeutic target, and outline past and ongoing hypoxia-targeted therapy trials in NSCLC. Evidence supporting radiotherapy dose painting based on hypoxia imaging will be critically appraised. Carefully selected hypoxia biomarkers suitable for integration within future NSCLC hypoxia-targeted therapy trials will be examined. Research gaps will be identified to guide future investigation. Although this review will focus on NSCLC hypoxia, more general discussions (eg, obstacles of hypoxia biomarker research and developing a framework for future hypoxia trials) are applicable to other tumor sites.