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Aquaculture (2020): 735986.

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Related Biological Data

The mRNA expression of OnBLNK in head kidney leukocytes incubated with anti-OnIgM mAb or pretreated with LYN / SYK / BTK inhibitor or solvent in vitro.
According to previous researches, the HKLs were treated with LYN inhibitor AZD0530 (0.5μM), SYK inhibitor P505-15 (2μM) and BTK inhibitor PCI-32765 (1μM, Glpbio, USA).
Aquaculture 531: 735986. PMID: 32109611 IF: 4.242

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Purity: >99.50%

实验参考方法

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.
References: [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.

产品描述

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].

References:
[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 &#181；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 &#181；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-1&#946；和 IL-18）的表达[9] ].

Chemical Properties

Cas No.	936563-96-1	SDF
别名	伊布替尼; PCI-32765
化学名	2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide
Canonical SMILES	C=CC(=O)N1CCCC(C1)N2C3=C(C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=NC=N3)N
分子式	C₂₅H₂₄N₆O₂	分子量	440.5
溶解度	≥ 22.025mg/mL in DMSO	储存条件	4°C, protect from light
General tips	请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。
Shipping Condition	评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。

溶解性数据

制备储备液
		1 mg	5 mg	10 mg
	1 mM	2.2701 mL	11.3507 mL	22.7015 mL
	5 mM	0.454 mL	2.2701 mL	4.5403 mL
	10 mM	0.227 mL	1.1351 mL	2.2701 mL

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Research Update

Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies

Purpose: Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and methods: Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion: Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia

B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.

Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials

Ibrutinib is a potent covalent kinase inhibitor that targets BTK. BTK, or Bruton's tyrosine kinase, is an obvious target for therapy of B cell diseases because inactivating mutations lead to B cell aplasia in humans and the disease X-linked agammaglobulinemia. Ibrutinib has modest cytotoxicity against CLL cells in vitro but also blocks trophic stimuli from the microenvironment. As with other inhibitors of the BCR pathway, ibrutinib causes rapid nodal reduction and response associated with rapid increase in lymphocytosis, which then returns to baseline over time. The ORR of ibrutinib in relapsed refractory CLL is 67 % with PFS 88 % at 15 months. In a cohort of untreated patients 65 years and over, the estimated 15 month PFS is 96 %. Registration trials have been initiated, and the difficult task that remains is to determine where in the course of CLL therapy this drug will have the greatest impact and benefit for patients.

PCI-32765 (Ibrutinib)

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