AMG-176
(Synonyms: AMG-176) 目录号 : GC19452
AMG-176 (Tapotoclax) 是一种有效的、选择性的、具有口服活性的 MCL-1 抑制剂，Ki 为 0.13 nM。
Cas No.:1883727-34-1
Sample solution is provided at 25 µL, 10mM.
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AMG-176 (Tapotoclax) is a potent, selective and orally active MCL-1 inhibitor, with a Ki of 0.13 nM.?AMG-176 is a potent antagonist of Mcl-1; in cell free system the Ki value is <1 nM. In whole cells, the drug was tested in different leukemias, lymphoma, and multiple myeloma cell lines[1]. AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death[4].AMG-176 induced cell death was inversely correlated with endogenous McL-1 levels[5].
AMG-176 has a weak ability to induce apoptosis in C002M melanoma cell line, but a strong ability to induce apoptosis in C057M melanoma cell line. AMG-176 has a synergistic effect with I-BET151 in these two melanoma cell lines[2]. AMG-176 completely neutralized the survival effect of the IDO1/Kyn/AHR pathway in CLL cells[6].
AMG-176 Is Efficacious in Multiple Myeloma. In vivo, Dose-dependent activation of the intrinsic apoptosis pathway in OPM-2 xenografts, as measured by activated BAK, cleaved caspase-3, and cleaved PARP, was detected as early as 2 hours after oral administration of AMG 176, with sustained cleaved PARP and activated BAK detectable through 12 hours and cleaved caspase-3 through 24 hours. Immunohistochemistry analysis revealed a similar dose-dependent increase in cleaved caspase-3[3].
References:
[1]:Garner TP, Lopez A, et,al. Progress in targeting the BCL-2 family of proteins. Curr Opin Chem Biol. 2017 Aug;39:133-142. doi: 10.1016/j.cbpa.2017.06.014. Epub 2017 Aug 17. PMID: 28735187; PMCID: PMC5667545.
[2]: Tseng HY, Dreyer J, et,al.Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma. Int J Cancer. 2020 Oct 15;147(8):2176-2189. doi: 10.1002/ijc.33000. Epub 2020 Apr 24. PMID: 32249419.
[3]: Caenepeel S, Brown SP,et,al. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies. Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub 2018 Sep 25. Erratum in: Cancer Discov. 2019 Jul;9(7):980. PMID: 30254093.
[4]:Yi X, Sarkar A, et,al. AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020 Jul 15;26(14):3856-3867. doi: 10.1158/1078-0432.CCR-19-1397. Epub 2020 Jan 14. PMID: 31937611; PMCID: PMC7358119.
[5]: Yi X, Jain N, et,al. Targeting Mcl-1 by AMG-176 During Ibrutinib and Venetoclax Therapy in Chronic Lymphocytic Leukemia. Front Oncol. 2022 Feb 22;12:833714. doi: 10.3389/fonc.2022.833714. PMID: 35273915; PMCID: PMC8901605.
[6]: Atene CG, Fiorcari S, et,al. Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation. Front Immunol. 2022 Mar 18;13:832263. doi: 10.3389/fimmu.2022.832263. PMID: 35371054; PMCID: PMC8971515.
AMG-176 (Tapotoclax) 是一种有效的、选择性的、具有口服活性的 MCL-1 抑制剂，Ki 为 0.13 nM。 AMG-176 是一种有效的 Mcl-1 拮抗剂；在无细胞系统中，Ki 值为 &<1 nM。在全细胞中，该药物在不同的白血病、淋巴瘤和多发性骨髓瘤细胞系中进行了测试[1]。 AMG-176 孵育导致时间和剂量依赖性 CLL 细胞死亡。在 100 和 300 nmol/L 时，24 小时时有 30% 和 45% 的细胞死亡。这些浓度不会导致正常造血细胞显着死亡。基质的存在不影响 AMG-176 诱导的 CLL 细胞死亡[4]。AMG-176 诱导的细胞死亡与内源性 McL-1 水平呈负相关[5] .
AMG-176对C002M黑色素瘤细胞系的凋亡诱导能力较弱，但对C057M黑色素瘤细胞系的凋亡诱导能力较强。 AMG-176 与 I-BET151 在这两种黑色素瘤细胞系中具有协同作用[2]。 AMG-176完全中和IDO1/Kyn/AHR通路对CLL细胞的存活效应[6]。
AMG-176 对多发性骨髓瘤有效。在体内，早在口服 AMG 176 后 2 小时就检测到 OPM-2 异种移植物中内在凋亡途径的剂量依赖性激活，如通过激活的 BAK、裂解的 caspase-3 和裂解的 PARP 所测量的，持续裂解PARP 和激活的 BAK 可在 12 小时内检测到，而裂解的 caspase-3 可在 24 小时内检测到。免疫组织化学分析表明，裂解的 caspase-3[3] 呈剂量依赖性增加。
| Cell experiment [1]: | |
|
Cell lines |
C002M and C057M melanoma cell lines |
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Preparation Method |
C002M and C057M were treated with the MCL1 inhibitor (AMG-176, 5 μM) for 72 hours and cell death was measured by Annexin V staining. |
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Reaction Conditions |
AMG-176 5uM; 72h |
|
Applications |
AMG-176 has a weak ability to induce apoptosis in C002M melanoma cell line, but a strong ability to induce apoptosis in C057M melanoma cell line. AMG-176 has a synergistic effect with I-BET151 in these two melanoma cell lines. |
| Animal experiment [2]: | |
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Animal models |
Human MCL1 Knock-In Mice |
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Preparation Method |
Ultiple myeloma cells (cell line OPM-2 luc) were injected s.c. in the right flank of mice (5 × 106 cells). Animals were randomized into groups (n = 10 per group). Animals were then orally administered with AMG-176 daily, 2×/week, or 1×/week. |
|
Dosage form |
10mg/kg;20 mg/kg;30 mg/kg; 60mg/kg. 2h-24h |
|
Applications |
Dose-dependent activation of the intrinsic apoptosis pathway in OPM-2 xenografts, as measured by activated BAK, cleaved caspase-3, and cleaved PARP, was detected as early as 2 hours after oral administration of AMG-176, with sustained cleaved PARP and activated BAK detectable through 12 hours and cleaved caspase-3 through 24 hours. Immunohistochemistry analysis revealed a similar dose-dependent increase in cleaved caspase-3. |
|
References: [1]. Tseng HY, Dreyer J, et,al.Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma. Int J Cancer. 2020 Oct 15;147(8):2176-2189. doi: 10.1002/ijc.33000. Epub 2020 Apr 24. PMID: 32249419. [2]. Caenepeel S, Brown SP,et,al. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies. Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub 2018 Sep 25. Erratum in: Cancer Discov. 2019 Jul;9(7):980. PMID: 30254093. |
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| Cas No. | 1883727-34-1 | SDF | |
| 别名 | AMG-176 | ||
| Canonical SMILES | ClC1=CC=C2C(CCC[C@@]23CN(C[C@@](CC4)([H])[C@]4([H])[C@H](/C=C/C[C@H](C)[C@H]5C)OC)C6=CC(C(NS5(=O)=O)=O)=CC=C6OC3)=C1 | ||
| 分子式 | C33H41ClN2O5S | 分子量 | 613.21 |
| 溶解度 | Soluble 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 | 1.6308 mL | 8.1538 mL | 16.3076 mL |
| 5 mM | 0.3262 mL | 1.6308 mL | 3.2615 mL |
| 10 mM | 0.1631 mL | 0.8154 mL | 1.6308 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
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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