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 Experiment | |
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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 Experiment | |
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Animal models | T-474 tumor xenografts in nude mice |
Formulation | 0.5% methyl cellulose |
Dosages | 30 mg/kg qd for 2 weeks |
Administration | PO. |
Molecular Weight | 480.41 |
Formula | C21H23Cl2N5O2S |
CAS Number | 847559-80-2 |
Solubility (25°C) | Ethanol 96 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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