BIIB021 化学構造
分子量: 318.76

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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 presence of serially diluted BIIB021 for 16 hours. Following incubation, cells are rinsed with PBS and then trypsinized. After stopping the trypsin reaction with fetal bovine serum, the cell suspensions are washed in PBS containing 0.2% bovine serum albumin and 0.2% sodium azide (BA buffer) and then resuspended in 100 μL phycoerythrin-conjugated anti-HER-2 IgG antibody. Untreated cells are resuspended in anti-KLH antibody as background controls. Cells are incubated 15 min at room temperature, washed twice in 200 μL BA buffer, resuspended in 200 μL BA buffer, and transferred to 5 mL round polystyrene tubes. An additional 250 μL BA buffer is then added to each tube. Samples are analyzed using a FACSCalibur flow cytometer equipped with argon-ion laser that emits 15 mW of 488 nm light for excitation of the phycoerythrin fluorochrome.

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
1

参考

化学情報

Download BIIB021 SDF
分子量 318.76
化学式

C14H15ClN6O

CAS No. 848695-25-0
別名 CNF2024
溶解度 (25°C)
  • DMSO 64 mg/mL
  • 水 <1 mg/mL
  • エタノール 2 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
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 (3)


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Rating
Source , , Acta Pharmacol Sin, 2013, 34(12):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.

Click to enlarge
Rating
Source , , Acta Pharmacol Sin, 2013, 34(12):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.

Click to enlarge
Rating
Source , , Acta Pharmacol Sin, 2013, 34(12):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 (3)

  • Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins. [Chen W, et al. PLoS Pathog 2012;8(11):e1003048]

    PubMed: 23209418
  • Hsp90 inhibition protect against biomechanically-induced osteoarthritis. [Siebelt M, et al. Arthritis Rheum 2013;65(8):2102-12]

    PubMed: 23666904
  • Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance. [Li M, et al. Acta Pharmacol Sin 2013;34(12):1545-53]

    PubMed: 24241349

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