Background
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].
参考文献:
[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。
Protocol
| Cell experiment [1]: |
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Cell lines
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C002M and C057M melanoma cell lines
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Preparation Method
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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
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AMG-176 5uM; 72h
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Applications
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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.
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| Animal experiment [2]: |
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Animal models
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Human MCL1 Knock-In Mice
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Preparation Method
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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.
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Dosage form
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10mg/kg;20 mg/kg;30 mg/kg; 60mg/kg. 2h-24h
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Applications
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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.
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参考文献:
[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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