规格 | 价格 | |
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500mg | ||
1g | ||
Other Sizes |
靶点 |
pIC50: 6.1 (BRD4), 6.3 (BRD2), 6.6 (BRD3)[1]
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体外研究 (In Vitro) |
用 1 μM 二盐酸盐 I-BET151 处理 72 小时后,大多数活细胞处于 G0 期,这与细胞增殖的剂量和时间依赖性减少以及溴脱氧尿苷掺入的消除相关。 2]。 I-BET151 二盐酸盐(100 nM;72 小时)以剂量和时间依赖性方式显着降低处于 S/G2 期的骨髓瘤细胞百分比[2]。
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体内研究 (In Vivo) |
I-BET151 二盐酸盐表现出良好的口服全身暴露,导致良好的口服生物利用度,但大鼠的血液清除率较差(约 20% 肝血流量)。在狗中,清除率很高(大约 95% 的肝脏血流量)。狗的全身暴露有限,导致口服生物利用度较差,仅为 16%。虽然大鼠和小鼠的低内在清除率(小鼠 IVC 1.6 mL/min/g;CLb 8 mL/min/kg)与这些物种的体内血液清除率较低相一致,但狗的高血液清除率与高在狗微粒体和肝细胞中观察到内在清除率。 I-BET151 二盐酸盐在小型猪中作为可能的第二种毒理学研究物种进行了检查,因为狗的全身暴露量较低,并且清除率较低(约 32% 肝血流量)和良好的生物利用度(65%)[ 1]。与用媒介物治疗的小鼠相比,用 I-BET151 二盐酸盐(30 mg/kg;腹腔注射;每天 21 天)治疗的小鼠的骨髓瘤肿瘤小了四到五倍,而且肿瘤大小倍增的速度也低得多[2] 。
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酶活实验 |
根据文献报道方法[J.Med.Chem.,54(2011),p.3827],在BRD2、BRD3和BRD4荧光各向异性(FP)测定中评估了化合物的靶点结合活性。异恶唑喹啉类似物与FP配体竞争,以亚微摩尔IC50与溴结构域结合,如表1所示。通过浸泡在BRD2 N-末端溴结构域的晶体中,获得了化合物1的1.8Å分辨率X射线晶体结构,6揭示了其结合模式(图1A)[1]。
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细胞实验 |
细胞活力测定[2]
细胞类型: H929 细胞 测试浓度: 1 μM 孵育时间: 72 hrs(小时) 实验结果:显示大多数活细胞处于 G0 期,并与细胞增殖的剂量和时间依赖性减少以及溴脱氧尿苷掺入的废除相称。 细胞增殖测定[2] 细胞类型: H929 细胞 测试浓度: 100 nM 孵育时间: 72 hrs(小时) 实验结果:引起 S/G2 期骨髓瘤细胞比例的显着剂量和时间依赖性下降。 |
动物实验 |
Animal/Disease Models: Mice (model of subcutaneous (sc)myeloma)[2]
Doses: 50 mg/kg Route of Administration: Ip; daily for 21 days Experimental Results: diminished rate of tumor size doubling than vehicle-treated mice. |
参考文献 |
[1]. Seal J, et al. Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72.
[2]. Chaidos A, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014 Jan 30;123(5):697-705. [3]. I-BET151 inhibits expression of RANKL, OPG, MMP3 and MMP9 in ankylosing spondylitis in vivo and in vitro. Exp Ther Med . 2017 Nov;14(5):4602-4606. |
其他信息 |
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.[1]
The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.[2] Ankylosing spondylitis (AS) is characterized by osteoclastogenesis and inflammatory bone resorption. The present study aimed to investigate the effect of bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 on AS process. A total of 38 AS Chinese patients were recruited and a further 38 sex- and age-matched healthy participants were selected as control. The Bath AS Function Index and Bath AS Disease Activity Index were assessed in AS patients and levels of erythrocyte sedimentation rate and C-reactive protein were measured in AS and healthy groups. Serum from AS patients was used to induce MG63 osteoblasts and BET inhibitor I-BET151 at concentrations of 50, 100 and 200 ng/ml used for treatment of the cells. A HLA-B27/β2m transgenic AS Lewis rat model was established and treated with 30 mg/kg I-BET151 for 5 weeks. Levels of receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and MMP9 were measured using ELISA in vivo and additionally detected with western blotting and polymerase chain reaction in vitro. The levels of RANKL, OPG, MMP3 and MMP9 were upregulated in AS serum, AS serum treated MG63 cells and HLA-B27/β2m transgenic AS rats. Conversely, levels of RANKL, OPG, MMP3 and MMP9 were significantly inhibited in cells or animals treated with I-BET151. Overall, the results of the present study demonstrated that BET inhibitor I-BET151 suppresses levels of RANKL, OPG, MMP3 and MMP9 in AS in vivo and in vitro. I-BET151 may exhibit the potential to be used as a therapeutic in the treatment of AS patients.[3] |
分子式 |
C23H23CL2N5O3
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分子量 |
488.37
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精确质量 |
487.117
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CAS号 |
1883545-47-8
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相关CAS号 |
I-BET151;1300031-49-5
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PubChem CID |
121513850
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外观&性状 |
Typically exists as solids
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LogP |
UFLKDZBLUNJNJS-FFXKMJQXSA-N
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tPSA |
93.4Ų
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SMILES |
[C@@H](C1N=CC=CC=1)(N1C(NC2C=NC3=CC(C4=C(ON=C4C)C)=C(OC)C=C3C1=2)=O)C.Cl
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InChi Key |
UFLKDZBLUNJNJS-FFXKMJQXSA-N
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InChi Code |
InChI=1S/C23H21N5O3.2ClH/c1-12-21(14(3)31-27-12)16-9-18-15(10-20(16)30-4)22-19(11-25-18)26-23(29)28(22)13(2)17-7-5-6-8-24-17;;/h5-11,13H,1-4H3,(H,26,29);2*1H/t13-;;/m1../s1
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化学名 |
7-(3,5-dimethyl-1,2-oxazol-4-yl)-8-methoxy-1-[(1R)-1-pyridin-2-ylethyl]-3H-imidazo[4,5-c]quinolin-2-one;dihydrochloride
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别名 |
I-BET 151 dihydrochloride; 1883545-47-8; I-BET151Dihydrochloride; I-BET151 (dihydrochloride); 7-(3,5-dimethyl-1,2-oxazol-4-yl)-8-methoxy-1-[(1R)-1-pyridin-2-ylethyl]-3H-imidazo[4,5-c]quinolin-2-one;dihydrochloride;
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HS Tariff Code |
2934.99.9001
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存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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溶解度 (体外实验) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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溶解度 (体外实验) |
注意: 如下所列的是一些常用的体内动物实验溶解配方,主要用于溶解难溶或不溶于水的产品(水溶度<1 mg/mL)。 建议您先取少量样品进行尝试,如该配方可行,再根据实验需求增加样品量。
注射用配方
注射用配方1: DMSO : Tween 80: Saline = 10 : 5 : 85 (如: 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)(IP/IV/IM/SC等) *生理盐水/Saline的制备:将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中,得到澄清溶液。 注射用配方 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (如: 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline) 注射用配方 3: DMSO : Corn oil = 10 : 90 (如: 100 μL DMSO → 900 μL Corn oil) 示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液,加到 900 μL Corn oil/玉米油中, 混合均匀。 View More
注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如:100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)] 口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠) 口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素) 示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中,得到0.5%CMC-Na澄清溶液;然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中,得到悬浮液。 View More
口服配方 3: 溶解于 PEG400 (聚乙二醇400) 请根据您的实验动物和给药方式选择适当的溶解配方/方案: 1、请先配制澄清的储备液(如:用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液,按从左到右的顺序依次添加助溶剂,澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明,并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀/澄清;向上述体系中加入50 μL Tween-80,混合均匀/澄清;然后继续加入450 μL ddH2O (或 saline)定容至 1 mL; 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出,可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果,工作液请现配现用! 6、如不确定怎么将母液配置成体内动物实验的工作液,请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
制备储备液 | 1 mg | 5 mg | 10 mg | |
1 mM | 2.0476 mL | 10.2381 mL | 20.4763 mL | |
5 mM | 0.4095 mL | 2.0476 mL | 4.0953 mL | |
10 mM | 0.2048 mL | 1.0238 mL | 2.0476 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液):对于大多数产品,InvivoChem推荐用DMSO配置母液 (比如:5、10、20mM或者10、20、50 mg/mL浓度),个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息,或者很难将产品溶解在溶液中,请联系我们;
3、建议使用下列计算器进行相关计算(摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等);
4、母液配好之后,将其分装到常规用量,并储存在-20°C或-80°C,尽量减少反复冻融循环。
计算结果:
工作液浓度: mg/mL;
DMSO母液配制方法: mg 药物溶于 μL DMSO溶液(母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度,请首先与我们联系。
体内配方配制方法:取 μL DMSO母液,加入 μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入 μL ddH2O,混匀澄清。
(1) 请确保溶液澄清之后,再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶;
(2) 一定要按顺序加入溶剂 (助溶剂) 。