BIIB021

Catalog No.S1175 Batch:S117504

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Technical Data

Formula

C14H15ClN6O
Molecular Weight 318.76 CAS No. 848695-25-0
Solubility (25°C)* In vitro DMSO 64 mg/mL (200.77 mM)
Ethanol 2 mg/mL (6.27 mM)
Water Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description BIIB021 (CNF2024) is an orally available, fully synthetic small-molecule inhibitor of HSP90 with Ki and EC50 of 1.7 nM and 38 nM, respectively. Phase 2.
Targets
HSP90 [1]
(Cell-free assay)
1.7 nM(Ki)
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. 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 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]

Protocol (from reference)

Kinase Assay:[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.
Cell Assay:[1]
  • Cell lines

    BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82 cells

  • Concentrations

    3 nM - 1 μM

  • Incubation Time

    5 days

  • Method

    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
Animal Study:[1]
  • Animal Models

    N87, BT474, CWR22, U87, SKOV3 and Panc-1 tumor models in BALB/c and athymic mice

  • Dosages

    31, 62.5, and 125 mg/kg

  • Administration

    Orally administered once daily

Customer Product Validation

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]

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

Selleck's BIIB021 has been cited by 33 publications

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain [ EJNMMI Radiopharm Chem, 2024, 9(1):19] PubMed: 38436869
m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress [ Cell Rep, 2022, 41(4):111546] PubMed: 36288717
deepOrganoid: A brightfield cell viability model for screening matrix-embedded organoids [ SLAS Discov, 2022, 27(3):175-184] PubMed: 35314378
The Disassociation of the A20/HSP90 Complex via Downregulation of HSP90 Restores the Effect of A20 Enhancing the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents [ Front Oncol, 2021, 11:804412] PubMed: 34976842
Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling [ Front Oncol, 2021, 11:620907] PubMed: 33738259
HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice. [ ACS Chem Neurosci, 2019, 10(6):2890-2902] PubMed: 31017387
Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy. [ SLAS Technol, 2019, 24(1):28-40] PubMed: 30289729
Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors [ Mol Syst Biol, 2018, 14(3):e7858] PubMed: 29507054
ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage. [Karayazi Atici, et al. Endocrinology, 2018, 159(2):907-930] PubMed: 29186352
The Toxmatrix: Chemo-Genomic Profiling Identifies Interactions That Reveal Mechanisms of Toxicity [ Chem Res Toxicol, 2018, 31(2):127-136] PubMed: 29156121

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