Lusutrombopag (S-888711)|1110766-97-6|安捷凯

Background

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]

参考文献:
[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]

Protocol

Cell experiment [1]:

Cell lines

pro-B-cell line(Ba/F3-hMpl cells，Ba/F3-mMpl cells)

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.

Reaction Conditions

pro-B-cell line were treated with Lusutrombopag (4.88–5000?nmol/L)for 72 h.

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]:

Animal models

Thrombocytopenia patients with hepatocellular carcinoma or chronic liver disease.

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.

Dosage form

3mg/day, oral

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.

参考文献:

[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.

安捷凯在线客服

扫一扫加微信

信号通路

生命科学

有机化学

无机化学

材料科学

Lusutrombopag (S-888711)

Lusutrombopag (S-888711)详情

Background

Protocol

安捷凯在线客服