Eltrombopag

Eltrombopag is a non-peptide thrombopoietin receptor (TPO-R) specific agonist with an EC₅₀ of 0.19µM for TPO-R^[1]. Eltrombopag mimics the biological function of natural thrombopoietin by activating the TPO-R signaling pathway and is primarily used in the treatment of immune thrombocytopenia and chemotherapy-induced thrombocytopenia. Additionally, Eltrombopag also has an inhibitory effect on the hERG potassium channel ^[2].

In in vitro cultures of normal CD34+ cells, Eltrombopag (3µg/mL; 4h) can bypass the inhibitory effect of IFN-γ on TPO intracellular signaling in human hematopoietic stem cells^[3]. In MEF cells, Eltrombopag (10μM; 6.5h) inhibited STS-induced, caspase-3/7 activity-mediated apoptosis in MEF cells expressing only BAX, but had no effect on MEF cells expressing only BAK ^[4]. In mouse embryonic fibroblasts, Eltrombopag (0–30μM; 24h) can bind to the BAK α4/α6/α7 groove to initiate BAK activation, inducing apoptosis that is dependent on BAK but not BAX ^[5].

In murine transplantation models of leukemia，Eltrombopag (0.4-1.0mg/mL; po; 50d) treatment significantly improved survival in these mice, and engrafted leukemia cells in Eltrombopag -treated mice showed increased CD11b and CD14 expression^[6]. In a mouse model of immune-mediated bone marrow failure, Eltrombopag（20μg/g/d; ip; 10d） significantly downregulated cytokines associated with Th1 immune responses and upregulated cytokines associated with Th2 immune responses^[7].

References:
[1]. Subbarayan R, Srinivasan D, Sadullah Usmani S, et al. Molecular insights on Eltrombopag: potential mitogen stimulants, angiogenesis, and therapeutic radioprotectant through TPO-R activation[J]. Platelets, 2024, 35(1): 2359028.
[2]. Pathak S, Roth M, Verma A, et al. Eltrombopag for the treatment of thrombocytopenia in patients with malignant and non-malignant hematologic disorders[J]. Expert opinion on drug metabolism & toxicology, 2013, 9(12): 1667-1675.
[3]. Alvarado L J, Huntsman H D, Cheng H, et al. Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ[J]. Blood, The Journal of the American Society of Hematology, 2019, 133(19): 2043-2055.
[4]. Spitz A Z, Zacharioudakis E, Reyna D E, et al. Eltrombopag directly inhibits BAX and prevents cell death[J]. Nature communications, 2021, 12(1): 1134.
[5]. Chen M, Hu L, Bao X, et al. Eltrombopag directly activates BAK and induces apoptosis[J]. Cell Death & Disease, 2023, 14(7): 394.
[6]. Roth M, Will B, Simkin G, et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation[J]. Blood, The Journal of the American Society of Hematology, 2012, 120(2): 386-394.
[]. Ding S, Liang X, Zhang T, et al. The effectiveness of rapamycin combined with Eltrombopag in murine models of immune‐mediated bone marrow failure[J]. Journal of Immunology Research, 2020, 2020(1): 1798795.

Eltrombopag是一种非肽类血小板生成素受体特异性激动剂，其对TPO-R的半数有效浓度（EC₅₀）为0.19µM^[1]。该药物通过激活TPO-R信号通路模拟天然血小板生成素的生物学功能，主要用于治疗免疫性血小板减少症和化疗相关性血小板减少症的研究。Eltrombopag对hERG钾通道也具有抑制作用^[2]。

在正常CD34⁺细胞的体外培养体系中，Eltrombopag（3µg/mL；4h）可逆转γ-干扰素对人造血干细胞TPO细胞内信号通路的抑制作用^[3]。在MEF细胞中，Eltrombopag（10μM；6.5h）显著抑制了STS诱导的、caspase-3/7活性介导的细胞凋亡，但该作用仅限于仅表达BAX的MEF细胞，在仅表达BAK的MEF细胞中未观察到明显影响^[4]。在小鼠胚胎成纤维细胞中，Eltrombopag（0-30μM；24h）能够结合BAK蛋白的α4/α6/α7结构沟槽，从而启动BAK活化过程，诱导仅依赖于BAK而非BAX的细胞凋亡途径^[5]。

在白血病小鼠移植模型中，Eltrombopag（0.4-1.0mg/mL；po；50d）治疗显著提高荷瘤小鼠生存率，移植白血病细胞中CD11b与CD14表达水平上调^[6]。在免疫性骨髓衰竭小鼠模型中，Eltrombopag（20μg/g/d；ip；10d）显著下调Th1免疫反应相关细胞因子，同时上调Th2免疫反应相关细胞因子^[7]。