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    BIIB021
    BIIB021

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0877
    CAS #: 848695-25-0 Purity ≥98%

    Description: BIIB021 (CNF2024; BIIB-021; CNF-2024; CNF 2024; BIIB 021) is an orally bioavailable and purine-based small-molecule inhibitor of HSP90 (heat shock protein 90) with potential anticancer activity. It inhibits HSP90 with a Ki and an EC50 of 1.7 nM and 38 nM, respectively.  BIIB021 exhibits excellent in vivo antitumor efficacy in many tumor xenograft models such as N87, BT474, CWR22, U87, SKOV3 and Panc-1.

    References: Mol Cancer Ther. 2009 Apr;8(4):921-9; Clin Cancer Res. 2009 Aug 15;15(16):5108-16; Int J Cancer. 2010 Mar 1;126(5):1216-25.

    Related CAS: 848695-25-0 (free base); 1225041-97-3 (mesylate)

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    • 香港大学
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    Molecular Weight (MW)318.76
    Formula

    C14H15ClN6O

    CAS No.848695-25-0(free base); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 64 mg/mL (200.8 mM)
    Water: <1 mg/mL
    Ethanol: 2 mg/mL (6.27 mM)
    Solubility (In vivo)30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
    SynonymsCNF2024; BIIB-021; CNF-2024; CNF 2024; BIIB021; BIIB 021; 

    Chemical Name: [6-Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-yl]amine

    InChi Key: QULDDKSCVCJTPV-UHFFFAOYSA-N

    InChi Code: InChI=1S/C14H15ClN6O/c1-7-4-17-9(8(2)11(7)22-3)5-21-6-18-10-12(15)19-14(16)20-13(10)21/h4,6H,5H2,1-3H3,(H2,16,19,20)

    SMILES Code: NC1=NC(Cl)=C2N=CN(CC3=NC=C(C)C(OC)=C3C)C2=N1


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    In Vitro

    In vitro activity: 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. 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. 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. 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.).


    Kinase 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.


    Cell Assay: 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 viability.

    In VivoOral administration of BIIB021 leads to tumor growth inhibition in many tumor xenograft models including N87, BT474, CWR22, U87, SKOV3 and Panc-1. BIIB021 effectively inhibits growth of L540cy tumor at a dose of 120 mg/kg. BIIB021 significantly enhances antitumor growth effect of radiation in JHU12 xenograft.
    Animal modelN87, BT474, CWR22, U87, SKOV3 and Panc-1 tumor models in BALB/c and athymic mice
    Formulation & DosageDissolved in Phospho-lipon/sucrose emulsion; 31, 62.5, and 125 mg/kg; oral gavage
    References

    Mol Cancer Ther. 2009 Apr;8(4):921-9; Clin Cancer Res. 2009 Aug 15;15(16):5108-16; Int J Cancer. 2010 Mar 1;126(5):1216-25.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    BIIB021

    BIIB021 selectively targets Hodgkin's lymphoma cells and inhibits constitutionally active NF-κB independent of functional IκB. Clin Cancer Res. 2009 Aug 15;15(16):5108-16.
     

    BIIB021

    BIIB021 inhibits Hodgkin's lymphoma cell viability in vitro synergistically with doxorubicin and gemcitabine.


    BIIB021

    HSP90 inhibition sensitizes L428 Hodgkin's lymphoma cells for NK cell–mediated cytotoxicity. Clin Cancer Res. 2009 Aug 15;15(16):5108-16.
     

    BIIB021

    HSP90 inhibition impairs Hodgkin's lymphoma tumor growth in vivo. Clin Cancer Res. 2009 Aug 15;15(16):5108-16.


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