BIIB021

製品コードS1175 バッチS117504

印刷

化学情報

Chemical Structure Synonyms CNF2024 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C14H15ClN6O
分子量 318.76 CAS No. 848695-25-0
Solubility (25°C)* 体外 DMSO 64 mg/mL (200.77 mM)
Ethanol 2 mg/mL (6.27 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 BIIB021 (CNF2024)は、経口投与可能な完全合成の低分子HSP90阻害剤であり、Kiは1.7 nM、EC50は38 nMです。現在フェーズ2。
in vitro BIIB021 binds in the ATP-binding pocket of Hsp90, interferes with Hsp90 chaperone function, and results in client protein degradation and tumor growth inhibition. This compound inhibits tumor cell (BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82) proliferation with IC50 from 0.06-0.31 μM. It 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. This chemical inhibits Hodgkin's lymphoma cells (KM-H2, L428, L540, L540cy, L591, L1236 and DEV) with IC50 from 0.24-0.8 μM. It shows low activity in lymphocytes from healthy individuals. This compound inhibits the constitutive activity of NF-κB despite defective IκB. It 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. This chemical 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. It is considerably more active than 17-AAG against adrenocortical carcinoma H295R, both in vitro and in vivo. The cytotoxic activity of this compound 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. It is also active in 17-AAG resistant cell lines (NIH-H69, MES SA Dx5, NCI-ADR-RES, Nalm6 and etc.).
in vivo Oral administration of BIIB021 leads to tumor growth inhibition in many tumor xenograft models including N87, BT474, CWR22, U87, SKOV3 and Panc-1. This compound effectively inhibits growth of L540cy tumor at a dose of 120 mg/kg. It significantly enhances antitumor growth effect of radiation in JHU12 xenograft.

プロトコル(参考用のみ)

キナーゼアッセイ 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, this compound 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 this chemical or no Hsp90, respectively. The data are fit to a four-parameter curve and IC50 is generated.
細胞アッセイ 細胞株 BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82 cells
濃度 3 nM - 1 μM
反応時間 5 days
実験の流れ 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. This compound 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 動物モデル N87, BT474, CWR22, U87, SKOV3 and Panc-1 tumor models in BALB/c and athymic mice
投薬量 31, 62.5, and 125 mg/kg
投与方法 Orally administered once daily

参考

  • https://pubmed.ncbi.nlm.nih.gov/19372565/
  • https://pubmed.ncbi.nlm.nih.gov/19671844/
  • https://pubmed.ncbi.nlm.nih.gov/19662650/
  • https://pubmed.ncbi.nlm.nih.gov/19676042/

カスタマーフィードバック

Data from [Acta Pharmacol Sin, 2013, 34(12), 1545-53]

Data from [Acta Pharmacol Sin, 2013, 34(12), 1545-53]

Data from [Acta Pharmacol Sin, 2013, 34(12), 1545-53]

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長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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