Ibrutinib (Synonyms: 伊布替尼; PCI-32765)
Ibrutinib (PCI-32765) 是一種不可逆的選擇性 Btk 抑制劑，IC50 值為 0.5 nM。Ibrutinib 可作為 Btk 配體，用于合成一系列 PROTAC 分子，如 P13I。P13I 作用于人 Burkitt’s 淋巴瘤 RAMOS 細(xì)胞，濃度為 10 和 100?nM 時(shí)，分別降解 73% 和 89% Btk。
生物活性
Ibrutinib (PCI-32765) is a selective, irreversible Btk inhibitor with an IC50 of 0.5 nM[1].
IC50 & Target
IC50: 0.5 nM (Btk)
體外研究(In Vitro)
Ibrutinib (PCI-32765) selectively inhibits B-cell signaling and activation. It inhibits autophosphorylation of Btk (IC50=11 nM), phosphorylation of Btk's physiological substrate PLCγ (IC50=29 nM), and phosphorylation of a further downstream kinase, ERK (IC50=13 nM)[1].
Ibrutinib (PCI-32765) inhibits BCR-activated primary B cell proliferation (IC50=8 nM). Following FcγR stimulation, Ibrutinib (PCI-32765) inhibits TNFα, IL-1β and IL-6 production in primary monocytes (IC50=2.6, 0.5, 3.9 nM, respectively)[3].
Ibrutinib binds C481 (Cysteine481) of BTK with an ideal IC50 of 0.5?nM. Ibrutinib cannot form a covalent bond with the hydroxyl group of serine, C481S mutation increases the IC50 against BTK-C481S phosphorylation from 2.2?nM to 1?μM[4].
體內(nèi)研究(In Vivo)
Ibrutinib (PCI-32765) (3.125-50 mg/kg, p.o.) reduces the level of circulating autoantibodies and completely suppresses disease in mice with collagen-induced arthritis. Ibrutinib (PCI-32765) inhibits autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Ibrutinib (PCI-32765) (3.125-50 mg/kg, p.o.) reduces renal disease and autoantibody production in MRL-Fas(lpr) mice[1]. Ibrutinib (PCI-32765) (0.1 μM) inhibits activation-induced proliferation of CLL cells, induces selective cytotoxicity in B cells compared with T cells, but alters activation induced T-cell cytokine production[2]. Ibrutinib (PCI-32765) dose-dependently and potently reverses arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. Ibrutinib (PCI-32765) also prevents clinical arthritis in CAIA models[3].
分子量：440.50
性狀：Solid
Formula：C25H24N6O2
CAS 號(hào)：936563-96-1
中文名稱(chēng)：依魯替尼；伊布魯替尼；伊布替尼
運(yùn)輸條件：Room temperature in continental US; may vary elsewhere.
儲(chǔ)存方式
4°C, protect from light
*In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)
溶解性數(shù)據(jù)
DMSO : 100 mg/mL (227.01 mM; Need ultrasonic)
| 濃度溶劑體積質(zhì)量 | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.2701 mL | 11.3507 mL | 22.7015 mL |
| 5 mM | 0.4540 mL | 2.2701 mL | 4.5403 mL |
| 10 mM | 0.2270 mL | 1.1351 mL | 2.2701 mL |
請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；一旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。
儲(chǔ)備液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (protect from light)。-80°C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)月內(nèi)使用，-20°C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)月內(nèi)使用。
以下溶解方案都請(qǐng)先按照 In Vitro 方式配制澄清的儲(chǔ)備液，再依次添加助溶劑：
——為保證實(shí)驗(yàn)結(jié)果的可靠性，澄清的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的工作液，建議您現(xiàn)用現(xiàn)配，當(dāng)天使用； 以下溶劑前顯示的百
分比是指該溶劑在您配制終溶液中的體積占比；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的方式助溶
- 1.
請(qǐng)依序添加每種溶劑： 0.5% MC 0.5% Tween-80
Solubility: 3.33 mg/mL (7.56 mM); Suspension solution; Need ultrasonic
- 2.
請(qǐng)依序添加每種溶劑： 5% DMSO 95% (20% SBE-β-CD in saline)
Solubility: ≥ 2.75 mg/mL (6.24 mM); Clear solution
- 3.
請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% saline
Solubility: ≥ 2.5 mg/mL (5.68 mM); Clear solution
- 4.
請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-β-CD in saline)
Solubility: 2.5 mg/mL (5.68 mM); Suspended solution; Need ultrasonic
- 5.
請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oil
Solubility: ≥ 2.5 mg/mL (5.68 mM); Clear solution
參考文獻(xiàn)
[1]. Honigberg LA, 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. [Content Brief]
[2]. Herman SE, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011 Jun 9;117(23):6287-96. [Content Brief]
[3]. Chang BY, et al. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 2011 Jul 13;13(4):R115. [Content Brief]
[4]. Sun Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018 Jul;28(7):779-781. [Content Brief]
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