Evobrutinib 作为一种口服、高选择性、共价的布鲁顿氏酪氨酸激酶抑制剂，具有良好的耐受性和有效性。
Evobrutinib, as an orally, highly selective, covalent Bruton's tyrosine kinase inhibitor, was well‐tolerated and effective.[1] Evobrutinib was metabolized via hydroxylation, hydrolysis, O-dealkylation, glucuronidation, and GSH conjugation.[4]
n vitro efficacy test it shown that evobrutinib inhibits Btk in vitro with IC50 values in two studies 58 nM and 38 nM. Evobrutinib at concentrations of 10 μM did not increase bleeding time in vitro. [5] In U937 NF-κB–Luc reporter cells, evobrutinib inhibited NF-κB activation and, FcγR signaling with an IC50 of 78 nM. Evobrutinib inhibited BTK and BMX with IC50 values of 0.058 μM and 0.02 μM, respectively. Evobrutinib inhibited B cell activation in PBMCs with a mean IC50 of 15.8 nM. Evobrutinib inhibited basophil activation with an average IC50 of 1.66 μM. [2] In vitro, treatment with 100 to 1000 nM evobrutinib dose-dependently reduced calcium mobilization upon BCR ligation in a manner indistinguishable from the murine setting, while T cells again remained unaffected. In addition, production of IL-6, IFN-γ and IL-10 upon BCR ligation was reduced by 1000 nM evobrutinib.[3]
In vivo, treatment with 1, 3 or 10 mg/kg evobrutinib in C57/BL6 mice orally inhibited expression of molecules involved in B-cell antigen presentation. Evobrutinib treatment (10 mg/kg) functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a remarkably decreased disease severity in mice.[3]
参考文献:
[1]Scheible H, et al. Evobrutinib, a covalent Bruton's tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants. Clin Transl Sci. 2021 Nov;14(6):2420-2430.?
[2]Haselmayer P, et al. Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models. J Immunol. 2019 May 15;202(10):2888-2906.
[3]Torke S, et al. Inhibition of Bruton's tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 2020 Oct;140(4):535-548.?
[4]Li Z, et al. Identification of metabolites of evobrutinib in rat and human hepatocytes by using ultra-high performance liquid chromatography coupled with diode array detector and Q Exactive Orbitrap tandem mass spectrometry. Drug Test Anal. 2019 Jan;11(1):129-139.?
[5]von Hundelshausen P, et al. Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. Cancers (Basel). 2021 Mar 4;13(5):1103.
Evobrutinib 作为一种口服、高选择性、共价的布鲁顿氏酪氨酸激酶抑制剂，具有良好的耐受性和有效性。[1]Evobrutinib 通过羟基化、水解、O-脱烷基化、葡萄糖醛酸化和GSH 结合。[4]
体外药效试验表明，evobrutinib 在体外抑制 Btk，两项研究中的 IC50 值为 58 nM 和 38 nM。浓度为 10 μM 的 Evobrutinib 在体外不会增加出血时间。 [5] 在 U937 NF-κB-Luc 报告细胞中，evobrutinib 抑制 NF-κB 活化和 FcγR 信号，IC50 为 78 nM。 Evobrutinib 抑制 BTK 和 BMX，IC50 值分别为 0.058 μM 和 0.02 μM。 Evobrutinib 抑制 PBMC 中的 B 细胞活化，平均 IC50 为 15.8 nM。 Evobrutinib 抑制嗜碱性粒细胞活化，平均 IC50 为 1.66 μM。 [2] 在体外，100 至 1000 nM evobrutinib 剂量依赖性地减少了 BCR 结扎时的钙动员，其方式与鼠类设置没有区别，而 T 细胞再次保持不受影响。此外，1000 nM evobrutinib 减少了 BCR 连接时 IL-6、IFN-γ 和 IL-10 的产生。[3]
在体内，C57/BL6 小鼠口服 1、3 或 10 mg/kg evobrutinib 可抑制参与 B 细胞抗原呈递的分子的表达。 Evobrutinib 治疗 (10 mg/kg) 在功能上削弱了 B 细胞作为抗原呈递细胞的能力，从而促进了脑炎性 T 细胞的发育，从而显着降低了小鼠的疾病严重程度。[3]
| Cell experiment [1]: | |
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Cell lines |
B cells |
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Preparation Method |
In a complementary in vitro setting, freshly isolated B cells from non-evobrutinib-treated mice were directly pre-incubated with evobrutinib doses up to 1 μM. |
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Reaction Conditions |
1 μM; 30min |
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Applications |
Evobrutinib specifically inhibits B cellular excitatory calcium mobilization and cytokine production. |
| Animal experiment [2]: | |
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Animal models |
DBA/1J female mice aged 11–12 wk |
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Preparation Method |
Mice were administered a single dose of 12 mg/kg evobrutinib, and B cell inhibition was measured as before at different time points. |
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Dosage form |
12 mg/kg; p.o. |
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Applications |
16 h after dosing, B cell activation was still inhibited by roughly 50%. |
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参考文献: [1]. Torke S, et al. Inhibition of Bruton's tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 2020 Oct;140(4):535-548. [2]. Haselmayer P, et al. Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models. J Immunol. 2019 May 15;202(10):2888-2906.? |
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