NVP-BEP800 (VER-82576) is an ATP-competitive HSP90β inhibitor. Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. NVP-BEP800 (VER-82576) showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf(V600E), Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 (VER-82576) showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. NVP-BEP800 can radiosensitise tumour cell lines of different entities through destabilisation and depletion of several Hsp90 client proteins, thus causing the depletion of S phase and G2/M arrest, increased DNA damage and repair protraction and, to some extent, apoptosis.
|Cell lines||BT-474, SKBr3, MCF-7, MDA-MB-157, MDA-MB-231, MDA-MB-468 and BT20 cells line|
|Preparation method||Cell proliferation was determined using either sulforhodamine B for adherent cells or MTS assay for suspension cells or those showing low adherence. GI50 was the compound concentration that inhibits cell growth by 50% compared with vehicle control.|
|Concentrations||0~1 μ M|
|Incubation time||24 h|
|Animal models||T-474 tumor xenografts in nude mice|
|Formulation||0.5% methyl cellulose|
|Dosages||30 mg/kg qd for 2 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.
|Solubility||Ethanol 96 mg/mL|
Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction.
Stingl L, et al. Br J Cancer. 2010 May 25;102(11):1578-91. PMID: 20502461.
Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.
Massey AJ, et al. Mol Cancer Ther. 2010 Apr;9(4):906-19. PMID: 20371713.
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