Lusutrombopag (S-888711)
(Synonyms: 芦曲泊帕; S-888711) 目录号 : GC31669
lusutrombopag 是一种具有口服生物利用度的小分子血小板生成素受体激动剂，已获准用于治疗计划接受手术的慢性肝病成年患者的血小板减少症。
Cas No.:1110766-97-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
pro-B-cell line(Ba/F3-hMpl cells，Ba/F3-mMpl cells) |
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Preparation Method |
Cells were cultured with Lusutrombopag for 72 h. 10 µL WST-8 reagent as added to each well during the last 2–8 hours of culture. The absorbance was measured at a wavelength of 450 nm using a 96-well microplate reader.Then cell viability was evaluated by proliferation assay. |
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Reaction Conditions |
pro-B-cell line were treated with Lusutrombopag (4.88–5000 nmol/L)for 72 h. |
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Applications |
Lusutrombopag promoted the proliferation of Ba/F3-hMpl cells. The 50% EC50 values of lusutrombopag in Ba/F3-hMpl cells were 84.0 nmol/L,whereas lusutrombopag exhibited no proliferative activity in Ba/F3-mMpl cells.These results indicate that lusutrombopag promotes the proliferation of Ba/F3-hMpl cells via human c-Mpl. |
| Animal experiment [2]: | |
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Animal models |
Thrombocytopenia patients with hepatocellular carcinoma or chronic liver disease. |
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Preparation Method |
Patients were randomized in a 1:1 ratio to receive either lusutrombopag or placebo once daily for 7 days or fewer before an invasive procedure performed 9 to 14 days after randomization. |
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Dosage form |
3mg/day, oral |
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Applications |
Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo. |
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References: [1]. Yoshida H, Yamada H, et al. Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. Exp Hematol. 2018 Mar;59:30-39.e2. [2]. Alkhouri N, Imawari M, et al. Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2600-2608.e1. |
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Lusutrombopag, an orally bioavailable, small molecule thrombopoietin receptor agonist, is approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure[1].
Lusutrombopag exhibits agonist activity for human thrombopoietin(TPO) receptor c-Mpl. Lusutrombopag promoted the proliferation of Ba/F3-hMpl cells. The 50% EC50 values of lusutrombopag Ba/F3-hMpl cells were 84.0, whereas lusutrombopag exhibited no proliferative activity in Ba/F3-mMpl cells. These results indicate that lusutrombopag promotes the proliferation of Ba/F3-hMpl cells via human c-Mpl. To investigate the signal transduction pathway of lusutrombopag, we evaluated the phosphorylation of JAK2, STAT3, STAT5 and p44/42 MAPK in Ba/F3-hMpl cells. Lusutrombopag phosphorylated these molecules similarly to rhTPO. These results suggest that lusutrombopag activates the same signal transduction pathways activated by rhTPO[2]
Lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration in TPOR-Ki/Shi mice, was developed by replacing mouse Mpl with human-mouse chimera Mpl. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production[2]
Lusutrombopag significantly increased the platelet count in all 31 patients with a mean increase of 31,000/μL.However, the increase in the platelet count after platelet transfusion was not statistically significant. When 13 patients repeated uses of lusutrombopag were counted platelet transfusion was not required in 82.1% (23/28) of treatments[3]
References:
[1]. Shirley M, McCafferty EH, et al. Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure. Drugs. 2019 Oct;79(15):1689-1695.
[2]. Yoshida H, Yamada H, et al. Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl. Exp Hematol. 2018 Mar;59:30-39.e2.
[3]. Nomoto H, Morimoto N, et al. Lusutrombopag is effective and safe in patients with chronic liver disease and severe thrombocytopenia: a multicenter retrospective study. BMC Gastroenterol. 2020 Dec 14;20(1):427.
lusutrombopag 是一种具有口服生物利用度的小分子血小板生成素受体激动剂,已获准用于治疗计划接受手术的慢性肝病成年患者的血小板减少症[1]。
Lusutrombopag 对人血小板生成素 (TPO) 受体 c-Mpl 具有激动剂活性。 Lusutrombopag 促进 Ba/F3-hMpl 细胞的增殖。 lusutrombopag Ba/F3-hMpl 细胞的 50% EC50 值为 84.0,而 lusutrombopag 在 Ba/F3-mMpl 细胞中没有表现出增殖活性。这些结果表明 lusutrombopag 通过人 c-Mpl 促进 Ba/F3-hMpl 细胞的增殖。为了研究 lusutrombopag 的信号转导通路,我们评估了 Ba/F3-hMpl 细胞中 JAK2、STAT3、STAT5 和 p44/42 MAPK 的磷酸化。 Lusutrombopag 磷酸化这些分子类似于 rhTPO。这些结果表明,lusutrombopag 激活的信号转导通路与 rhTPO[2]
Lusutrombopag 在 TPOR-Ki/Shi 小鼠中重复口服给药 21 天期间以剂量依赖性方式显着增加循环血小板,该药物是通过用人-小鼠嵌合体 Mpl 替换小鼠 Mpl 而开发的。在第 22 天对 TPOR-Ki/Shi 小鼠进行的组织病理学研究也揭示了骨髓中巨核细胞的显着增加。这些结果表明,lusutrombopag 作用于人 TPOR,上调巨核细胞的分化和增殖,导致血小板生成[2]
Lusutrombopag 显着增加了所有 31 名患者的血小板计数,平均增加了 31,000/μL。但是,血小板输注后血小板计数的增加没有统计学意义。当对 13 名重复使用 lusutrombopag 的患者进行计数时,82.1% (23/28) 的治疗不需要血小板输注[3]
| Cas No. | 1110766-97-6 | SDF | |
| 别名 | 芦曲泊帕; S-888711 | ||
| Canonical SMILES | O=C(O)/C(C)=C/C1=C(Cl)C=C(C(NC2=NC(C3=CC=CC([C@@H](OCCCCCC)C)=C3OC)=CS2)=O)C=C1Cl | ||
| 分子式 | C29H32Cl2N2O5S | 分子量 | 591.55 |
| 溶解度 | DMSO : ≥ 33 mg/mL (55.79 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 | 1.6905 mL | 8.4524 mL | 16.9047 mL |
| 5 mM | 0.3381 mL | 1.6905 mL | 3.3809 mL |
| 10 mM | 0.169 mL | 0.8452 mL | 1.6905 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。
Lusutrombopag
No information is available on the use of lusutrombopag during breastfeeding. The manufacturer recommends avoiding breastfeeding during the use of lusutrombopag and for at least 28 days after the last dose.
Development of a new knock-in mouse model and evaluation of pharmacological activities of lusutrombopag, a novel, nonpeptidyl small-molecule agonist of the human thrombopoietin receptor c-Mpl
Lusutrombopag (S-888711), an oral small-molecule thrombopoietin receptor (TPOR) agonist, has gained first approval as a drug to treat thrombocytopenia of chronic liver disease in patients undergoing elective invasive procedures in Japan. Preclinical studies were performed to evaluate its efficacy against megakaryopoiesis and thrombopoiesis. To investigate the proliferative activity and efficacy of megakaryocytic colony formation via human TPOR, lusutrombopag was applied to cultured human c-Mpl-expressing Ba/F3 (Ba/F3-hMpl) cells and human bone marrow-derived CD34-positive cells, respectively. Lusutrombopag caused a robust increase in Ba/F3-hMpl cells by activating pathways in a manner similar to that of thrombopoietin and induced colony-forming units-megakaryocyte and polyploid megakaryocytes in human CD34-positive cells. Because lusutrombopag has high species specificity for human TPOR, there was no suitable experimental animal model for drug evaluation, except for immunodeficient mouse-based xenograft models. Therefore, a novel genetically modified knock-in mouse, TPOR-Ki/Shi, was developed by replacing mouse Mpl with human-mouse chimera Mpl. In TPOR-Ki/Shi mice, lusutrombopag significantly increased circulating platelets in a dose-dependent manner during 21-day repeated oral administration. Histopathological study of the TPOR-Ki/Shi mice on day 22 also revealed a significant increase in megakaryocytes in the bone marrow. These results indicate that lusutrombopag acts on human TPOR to upregulate differentiation and proliferation of megakaryocytic cells, leading to platelet production.