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  • PCI-32765 (Ibrutinib)
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PCI-32765 (Ibrutinib)

PCI-32765 (Ibrutinib) is an irreversible selective inhibitor of Bruton s tyrosine kinase (BTK) that selectively targets its kinase domain.

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  • 货号: ajci11866
  • CAS: 936563-96-1
  • 别名: 伊布替尼; PCI-32765
  • 分子式: C25H24N6O2
  • 分子量: 440.5
  • 纯度: >98%
  • 溶解度: ≥ 22.025mg/mL in DMSO
  • 储存: 4°C, protect from light
  • 库存: 现货

Background

PCI-32765 (Ibrutinib) is an irreversible selective inhibitor of Bruton s tyrosine kinase (BTK) that selectively targets its kinase domain and modulates BTK downstream signaling by reducing its phosphorylating capacity with IC50 of 0.5 nM in cell-free assays [1,5,6]. Ibrutinib can cross the blood brain barrier, as shown in several preclinical reports[2]. As an immunomodulator, ibrutinib affects the function of peripheral innate and acquired immune cells, including macrophages,B cells,T cells, and natural killer cells[3,4].


Ibrutinib(1 μM;30 min) significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial cells. Ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling[4].Ibrutinib(1, 5, 10, 25, or 50 μmol/L for 24h) improved the decreased cell viability and attenuated oxidative stress in the high glucose incubated PC12 cells which subjected to H/R injury[8].


Ibrutinib(50 mg/kg/day; p.o.; 5 days) treatment significantly improved the immobility time, body weight, and sucrose preference induced by LPS, suggesting the antidepressant potential of ibrutinib[7]. Ibrutinib(50 mg/kg/d; i.g.) significantly inhibited the expression of pyroptosis related proteins (NLRP3, Caspase-1, Gasdermin D (GSDMD), IL-1β and IL-18) in the lung tissues of sepsis mice[9].

参考文献:
[1]. de Porto AP, Liu Z, et,al. Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia. Mol Med. 2019 Jan 15;25(1):3. doi: 10.1186/s10020-018-0069-7. PMID: 30646846; PMCID: PMC6332549.
[2]. Goldwirt L, Beccaria K, et,al. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018 Apr;81(4):783-789. doi: 10.1007/s00280-018-3546-3. Epub 2018 Feb 23. PMID: 29476222.
[3]. Grommes C, Pastore A, et,al. Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discov. 2017 Sep;7(9):1018-1029. doi: 10.1158/2159-8290.CD-17-0613. Epub 2017 Jun 15. PMID: 28619981; PMCID: PMC5581705.
[4]. Nam HY, Nam JH, et,al. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206.
[5]. Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013 Nov;54(11):2385-91. doi: 10.3109/10428194.2013.777837. Epub 2013 Aug 28. PMID: 23425038.
[6]. Honigberg LA, Smith AM, et,al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80. doi: 10.1073/pnas.1004594107. Epub 2010 Jul 6. PMID: 20615965; PMCID: PMC2919935.
[7]. Li W, Ali T, et,al. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression. Brain Behav Immun. 2021 Feb;92:10-24. doi: 10.1016/j.bbi.2020.11.008. Epub 2020 Nov 10. PMID: 33181270.
[8]. Jin L, Mo Y, et,al. Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice. Bioengineered. 2021 Dec;12(1):7432-7445. doi: 10.1080/21655979.2021.1974810. PMID: 34605340; PMCID: PMC8806753.
[9]. Tang H, Li H, et,al. Ibrutinib protects against acute lung injury via inhibiting NLRP3/Caspase-1 in septic mice model. Mol Immunol. 2022 Dec;152:232-239. doi: 10.1016/j.molimm.2022.11.006. Epub 2022 Nov 12. PMID: 36379131.


PCI-32765 (Ibrutinib) 是一种不可逆的选择性布鲁顿氏酪氨酸激酶 (BTK) 抑制剂,可选择性靶向其激酶结构域并通过降低其磷酸化能力来调节 BTK 下游信号传导,在无细胞试验中 IC50 为 0.5 nM [1 ,5,6]。伊布替尼可以穿过血脑屏障,如多个临床前报告所示[2]。作为一种免疫调节剂,伊布替尼影响外周先天性和获得性免疫细胞的功能,包括巨噬细胞、B 细胞、T 细胞和自然杀伤细胞[3,4]。


Ibrutinib(1 µ;M;30 分钟)显着降低 BV2 小胶质细胞中 LPS 诱导的促炎细胞因子水平升高。 Ibrutinib 还通过抑制 AKT 信号转导减少 LPS 诱导的 BV2 小胶质细胞迁移[4]。Ibrutinib(1、5、10、25 或 50 µ;mol/L 持续 24 小时)改善细胞活力降低并减弱氧化应激在高葡萄糖孵育 H/R 损伤的 PC12 细胞[8]。


Ibrutinib(50 mg/kg/天;口服;5 天)处理显着改善不动时间、体重和诱导的蔗糖偏好LPS,表明依鲁替尼的抗抑郁潜力[7]。 Ibrutinib(50 mg/kg/d;i.g)显着抑制脓毒症小鼠肺组织中细胞焦亡相关蛋白(NLRP3、Caspase-1、Gasdermin D (GSDMD)、IL-1β;和 IL-18)的表达[9] ].

Protocol

Cell experiment [1]:

Cell lines

BV2 microglial cells

Preparation Method

Cells were treated with PCI-32765 (Ibrutinib) (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses.

Reaction Conditions

1 μM;30 min

Applications

Ibrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial cells. Ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling.

Animal experiment [2]:

Animal models

Adult C57BL/6J male mice weighing 25-30g (age 12-14 weeks)

Preparation Method

The experimental animals were divided into four groups (each group = 10 animals): normal saline-treated (NC), LPS (2 mg/kg/day) treated (LPS), LPS + Ibrutinib (50 mg/kg/day) treated (LPS + IBR), and Ibrutinib (50 mg/kg/day) treated (IBR).

Dosage form

50 mg/kg/day; p.o.; 5 days

Applications

Ibrutinib attenuated LPS-induced depressive-like behaviors.

参考文献:

[1].Nam HY, Nam JH, et,al. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206.
[2]. Li W, Ali T, et,al. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression. Brain Behav Immun. 2021 Feb;92:10-24. doi: 10.1016/j.bbi.2020.11.008. Epub 2020 Nov 10. PMID: 33181270.

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