BIIB021 (CNF2024) is an orally available synthetic non-ansamycin Hsp90 inhibitor with ki value of 1.7nM. BIIB021 (CNF2024) selectively and potently inhibits the molecular chaperone Hsp90 thereby inhibiting the proper assembly of multiple oncogenic proteins involved in tumor growth and survival.BIIB021 (CNF2024) has antitumor activity in Hodgkin's lymphoma in vitro and in vivo. BIIB021 (CNF2024) selectively induced Hodgkin's lymphoma cell death but did not kill normal lymphocytes from healthy individuals. BIIB021 inhibited the activity of NF-κB, which was independent of IκB mutations.
|Source||Frontiers in Microbiology (2015). Figure 3. BIIB021|
|Method||cell apoptosis assay|
|Cell Lines||NK cell lines|
|Incubation Time||96 h|
|Results||BIIB021 increased early apoptotic cells,defined as those positive forannexin V and negative for 7 AAD staining, in the two T cell lines, SNT16 and Jurkat, and two NK cell lines, SNK6 and KHYG1.|
|Cell lines||N87, MCF-7 and BT474 cell lines|
|Preparation method||Cell Proliferation Assay.
A modified tetrazolium salt assay was used to measure the inhibition of tumor cell growth. Cells were added to 96-well plates and propagated for 24 h before compound addition. The compound was serially diluted and added at a concentration range of 3 to 1,000 nmol/L to the plated cells. DMSO (0.03-0.003%) was included as a vehicle control. Cells were incubated in the presence of compound for 5 days. 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; Promega) were 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 gave rise to a soluble formazan product that was secreted into the culture medium. After 4 h incubation, the formazan product was quantitated spectrophotometrically at a wavelength of 490 nm. Data were acquired using SOFTmaxPRO software, and 100% viability was 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 was calculated from the A490 values as follows: % viability = (A490 nm sample / A490 nm DMSO-treated cells × 100). The IC50 was defined as the concentration that gave rise to 50% inhibition of cell viability.
|Concentrations||3 ~ 1000 nM|
|Incubation time||5 days|
|Animal models||nude mice bearing N87 stomach carcinoma tumors xenograft model|
|Dosages||31, 62.5, and 125 mg/kg, once daily, from Monday to Friday, for 5 weeks|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors.
Dickson et al. Ann Oncol. 2012 Aug 16. PMID: 22898035.
In vitro metabolism of BIIB021, an inhibitor of heat shock protein 90, in liver microsomes and hepatocytes of rats, dogs, and humans and recombinant human cytochrome P450 isoforms.
Xu et al. Drug Metab Dispos. 2012 Apr;40(4):680-93. PMID: 22217465.
An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors.
Dakappagari et al. Biomarkers. 2010 Feb;15(1):31-8. PMID: 19747088.
BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.
Zhang et al. Int J Cancer. 2010 Mar 1;126(5):1226-34. PMID: 19676042.
BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.
Lundgren K, et al. Mol Cancer Ther. 2009 Apr;8(4):921-9. PMID: 19372565.
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