BIIB021 化学構造
分子量: 318.76

品質と確認

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Quality Control & MSDS

製品情報

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製品の説明

生物活性

情報 BIIB021は、Hsp90の新しい阻害剤で、 Ki と EC50 がそれぞれ 1.7 nM と 38 nMです。
目標 HSP90
IC50 1.7 nM (Ki) and 38 nM (EC50) [1]
In vitro試験 BIIB021 binds in the ATP-binding pocket of Hsp90, interferes with Hsp90 chaperone function, and results in client protein degradation and tumor growth inhibition. BIIB021 inhibits tumor cell (BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82) proliferation with IC50 from 0.06-0.31 μM. BIIB021 induces the degradation of Hsp90 client proteins including HER-2, Akt, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. [1] BIIB021 inhibits Hodgkin's lymphoma cells (KM-H2, L428, L540, L540cy, L591, L1236 and DEV) with IC50 from 0.24-0.8 μM. BIIB021 shows low activity in lymphocytes from healthy individuals. BIIB021 inhibits the constitutive activity of NF-κB despite defective IκB. BIIB021 induces the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell–mediated killing. [2] BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines (UM11B and JHU12) with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. [3] BIIB021 is considerably more active than 17-AAG against adrenocortical carcinoma H295R, both in vitro and in vivo. The cytotoxic activity of BIIB021 is not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. BIIB021 is also active in 17-AAG resistant cell lines (NIH-H69, MES SA Dx5, NCI-ADR-RES, Nalm6 and etc.). [4]
In vivo試験 Oral administration of BIIB021 leads to tumor growth inhibition in many tumor xenograft models including N87, BT474, CWR22, U87, SKOV3 and Panc-1. [1] BIIB021 effectively inhibits growth of L540cy tumor at a dose of 120 mg/kg. [2] BIIB021 significantly enhances antitumor growth effect of radiation in JHU12 xenograft. [3]
臨床試験 Phase II study in subjects with gastrointestinal stromal tumors has been completed.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Hsp90 Binding Assay For fluorescence polarization competition measurements, the FITC-geldanamycin probe (20 nM) is reduced with 2 mM TCEP at room temperature for 3 hours, after which the solution is aliquoted and stored at -80 °C until used. Recombinant human Hsp90α (0.8 nM) and reduced FITC-geldanamycin (2 nM) are incubated in a 96-well microplate at room temperature for 3 hours in the presence of assay buffer containing 20 mM HEPES (pH 7.4), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 2 mM DTT, 0.1 mg/mL BGG, and 0.1% (v/v) CHAPS. Following this preincubation, BIIB021 in 100% DMSO is then added to final concentrations of 0.2 nM to 10 μM (final volume 100 μL, 2% DMSO). The reaction is incubated for 16 hours at room temperature and fluorescence is then measured in an Analyst plate reader, excitation = 485 nm, emission = 535 nm. High and low controls contained no BIIB021 or no Hsp90, respectively. The data are fit to a four-parameter curve and IC50 is generated.
HER-2 Degradation Assay MCF-7 cells (5 × 105) in complete DMEM are seeded per well in 24-well plates. The cells are propagated for 24 hours before BIIB021 addition. BIIB021 (1 mM) is prepared in DMSO and serially diluted in complete DMEM. Cells are incubated in the pr

細胞アッセイ: [1]

細胞系 BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82 cells
濃度 3 nM - 1 μM
処理時間 5 days
方法 A modified tetrazolium salt assay is used to measure the IC50. Tumor cells are added to 96-well plates and propagated for 24 hours before BIIB021 addition. BIIB021 is added to the plated cells. DMSO (0.03-0.003%) is included as a vehicle control. After incubation phenazine methosulfate (stock concentration 1 mg/mL) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (stock concentration 2 mg/mL) are mixed at a ratio of 1:20 and added to each well of a 96-well plate. Reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt gives rise to a soluble formazan product that is secreted into the culture medium. After 4 hours incubation, the formazan product is quantitated spectrophotometrically at a wavelength of 490 nm. Data are acquired using SOFTmaxPRO software, and 100% viability is defined as the A490 of DMSO-treated cells stained with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (the mean A490 of cells treated with DMSO at a range of 0.03-0.003%). Percent viability of each sample is calculated from the A490 values as follows: % viability = (A490 nm sample / A490 nm DMSO-treated cells × 100). The IC50 is defined as the concentration that gives rise to 50% inhibition of cell viabilit

動物実験: [1]

動物モデル N87, BT474, CWR22, U87, SKOV3 and Panc-1 tumor models in BALB/c and athymic mice
製剤 Phospho-lipon/sucrose emulsion [2]
投薬量 31, 62.5, and 125 mg/kg
管理 Orally administered once daily
Solubility 30% propylene glycol, 5% Tween 80, 65% D5W 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download BIIB021 SDF
分子量 318.76
化学式

C14H15ClN6O

CAS No. 848695-25-0
保管 2年-20℃
6月-80℃in DMSO
別名 CNF2024
溶解度 (25°C) * In vitro DMSO 64 mg/mL (200.77 mM)
<1 mg/mL (<1 mM)
エタノール 2 mg/mL (6.27 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine

研究分野

カスタマーレビュー (9)


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Rating
Source PLoS Pathog, 2012, 8(11), e1003048. BIIB021 purchased from Selleck
Method IC50 assay
Cell Lines SLK-KSHV, L1T2, SLK and KS-IMM cells
Concentrations 0, 2, 4, 8, 16, 32 and 64 nM
Incubation Time 120 h
Results SLK-KSHV, L1T2, SLK and KS-IMM were treated separately with17-DMAG, PU-H71, AUY922, BIIB021 and NVP-BEP800. IC50values were determined based on real-time growth curves usingthe XCelligence system (Table 3). All Hsp90 inhibitors hadnanomolar IC50s.

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Rating
Source PLoS Pathog, 2012, 8(11), e1003048. BIIB021 purchased from Selleck
Method Colony formation assay
Cell Lines L1T2 cells
Concentrations 10-80 nM
Incubation Time two weeks
Results BIIB021 inhibitedcell growth with nanomolar IC50.

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Rating
Source Acta Pharmacol Sin, 2013, 34(12), 1545-53. BIIB021 purchased from Selleck
Method Western blot
Cell Lines Molt-4 cells
Concentrations 0-400 nM
Incubation Time 24 h
Results BIIB021 triggered a dose-dependent cleavage of caspase-8, -9, -3, and poly ADP ribose polymerase (PARP).

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Rating
Source Acta Pharmacol Sin, 2013, 34(12), 1545-53. BIIB021 purchased from Selleck
Method Western blot
Cell Lines Molt-4 cells
Concentrations 1-20 uM
Incubation Time 24 h
Results BIIB021 signifi-cantly inhibited CDK4/6 expression, whereas cyclinD1, a main component of cyclin D1/CDK complexes, was resistant to BIIB021, with no decrease in expression even at the highest dose (400 nmol/L). Significantly upregulated expression of p18, a CDK inhibitor, was observed in the BIIB021-treated Molt-4 compared to the untreated cells.

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Rating
Source Acta Pharmacol Sin, 2013, 34(12), 1545-53. BIIB021 purchased from Selleck
Method Western blot
Cell Lines Molt-4 cells
Concentrations 0-400 uM
Incubation Time 24 h
Results BIIB021 could decreased Akt protein expression and phosphorylation, MDM2 and phospho-MDM2 protein levels, p53 protein and phospho-p53 levels.

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Rating
Source Acta Pharmacol Sin, 2013, 34(12), 1545-53. BIIB021 purchased from Selleck
Method Western blot, cell surfacebiotinylation
Cell Lines HEK293 cells
Concentrations 0-400 uM
Incubation Time 24 h
Results Treatment of HEK293 cells with B-RAF inhibitor PLX-4720 was followed by a statistically significant decrease inNaPi-IIa cell membrane protein abundance as compared with HEK293 cells treated with vehicle alone. Thus, PLX-4720 treatment decreased NaPi-IIa cell membrane proteinabundance in HEK293 cells .

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Rating
Source Acta Pharmacol Sin, 2013, 34, 1545-53. BIIB021 purchased from Selleck
Method MTT assay
Cell Lines Molt-4 cells
Concentrations 25-200 nM
Incubation Time 24 h, 48 h, 72 h
Results BIIB021 effectively inhibited Molt-4 cell growth in a dose- and time-dependent manner.

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Rating
Source Acta Pharmacol Sin, 2013, 34, 1545-53. BIIB021 purchased from Selleck
Method flow cytometry
Cell Lines Molt-4 cells
Concentrations 0-200 nM
Incubation Time 24 h
Results BIIB021 inhibits Molt-4 cell proliferation by causing the accumulation of cells with a G1 DNA content.

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Rating
Source Acta Pharmacol Sin, 2013, 34, 1545-53. BIIB021 purchased from Selleck
Method flow cytometry
Cell Lines Molt-4 cells
Concentrations 0-800 nM
Incubation Time 24 h
Results The results of Annexin V staining showed that externalized PS, a characteristic of early apoptosis, was increased in the BIIB021-treated Molt-4 cells in a dose-dependent fashion.

製品表彰状 (5)

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