Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor with an IC50 value of 1.6nM[1]. Orelabrutinib can reduce the expression of BTK and Mcl-1, and interfere with the activities of the PI3K/AKT signaling pathway and the p38/MAPK signaling pathway[2]. Orelabrutinib has been widely used in mouse models to treat primary immune thrombocytopenia (ITP)[3].
In vitro, Orelabrutinib treatment for 72h significantly inhibited the viability of TMD8 cells, HBL-1 cells and SU-DHL-6 cells with IC50 values of 0.03μM, 0.17μM, and 1.89μM, respectively[4]. Treatment of SU-DHL-4 cells with 60μM Orelabrutinib combined with 2.5μM Chidamide for 48 hours significantly promoted cell apoptosis and induced cell cycle arrest[5]. Treatment with 2μM Orelabrutinib combined with 1μM Selinexor for 48 hours strongly inhibited the NF-κB, P-STAT3 and NFATc1 signaling pathways in OCI-LY10 cells and OCI-LY3 cells[6].
In vivo, Orelabrutinib treatment via oral administration at a dose of 10mg/kg/day for 28 days remarkablely reduced platelet phagocytosis and pro-inflammatory cytokine production in ITP mice[7]. In the TMD8 cell xenograft tumor mouse model, daily oral administration of 10mg/kg dose of Orelabrutinib for 3 weeks significantly inhibited tumor growth[4].
References:
[1] Zhang B, Zhao R, Liang R, et al. Abstract CT132: Orelabrutinib, a potent and selective Bruton's tyrosine kinase inhibitor with superior safety profile and excellent PK/PD properties[J]. Cancer Research, 2020, 80(16_Supplement): CT132-CT132.
[2] Pan G, Zhong M, Yao J, et al. Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling[J]. Journal of cancer research and clinical oncology, 2023, 149(9): 5513-5529.
[3] Yu T, Wang L, Ni X, et al. Orelabrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor in the treatment of primary immune thrombocytopenia (ITP)[J]. Blood, 2021, 138: 3172.
[4] Yu H, Wang X, Li J, et al. Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma[J]. Molecular Therapy-Oncolytics, 2021, 21: 158-170.
[5] Wu C, Chen S, Wu Z, et al. Chidamide and orelabrutinib synergistically induce cell cycle arrest and apoptosis in diffuse large B-cell lymphoma by regulating the PI3K/AKT/mTOR pathway[J]. Journal of Cancer Research and Clinical Oncology, 2024, 150(2): 98.
[6] Li L, Yang W, Ye R, et al. Combination of Selinexor with BTK Inhibitor for Central Nervous System Diffuse Large B-Cell Lymphoma, Possible Mechanisms and Therapeutic Potential Exploration[J]. Blood, 2023, 142: 3010.
[7] Yu T, Han S, Wang L, et al. Effects of orelabrutinib, a BTK inhibitor, on antibody‐mediated platelet destruction in primary immune thrombocytopenia[J]. British Journal of Haematology, 2025, 206(4): 1186-1199.
Orelabrutinib是一种口服给药的强效、不可逆、高选择性BTK抑制剂，IC50值为1.6nM[1]。Orelabrutinib可降低BTK和Mcl-1的表达，并干扰PI3K/AKT信号通路和p38/MAPK信号通路的活性[2]。Orelabrutinib已广泛用于小鼠模型，以治疗原发性免疫性血小板减少症(ITP)[3]。
在体外，Orelabrutinib处理72小时显著抑制了TMD8细胞、HBL-1细胞和SU-DHL-6细胞的活力，其IC50值分别为0.03μM、0.17μM和1.89μM[4]。用60μM的Orelabrutinib联合2.5μM的Chidamide处理SU-DHL-4细胞48小时，显著促进了细胞凋亡并诱导细胞周期停滞[5]。用2μM的Orelabrutinib联合1μM塞利尼索处理OCI-LY10细胞和OCI-LY3细胞48小时，强烈抑制了NF-κB、P-STAT3和NFATc1信号通路[6]。
在体内，以10mg/kg/day的剂量口服给予Orelabrutinib治疗28天，显著减少了ITP小鼠的血小板吞噬和促炎细胞因子产生[7]。在TMD8细胞异种移植瘤小鼠模型中，每日口服10mg/kg剂量的Orelabrutinib，持续3周，显著抑制了肿瘤生长[4]。