product name NVP-BEP800
Description: NVP-BEP800, also known as BEP-800 and VER82576, is a novel, fully synthetic, orally bioavailable HSP90β inhibitor with IC50 of 58 nM, it exhibits>70-fold selectivity against Hsp90 family members Grp94 and Trap-1. NVP-BEP800 binds to the NH(2)-terminal ATP-binding pocket of Hsp90. NVP-BEP800 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.
References: Mol Cancer Ther. 2010 Apr;9(4):906-19.
480.41
Formula
C21H23Cl2N5O2S
CAS No.
847559-80-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 15 mg/mL (31.2 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
0.5% methylcellulose: 5 mg/mL
Synonyms
VER82576
other peoduct :
| In Vitro |
In vitro activity: NVP-BEP800 is an ATP-competitive inhibitor of Hsp90β with an IC50 of 58 nM, exhibiting >70-fold selectivity against Hsp90 family members Grp94 and Trap-1 with IC50 values of 4.1 μM and 5.5 μM, respectively. NVP-BEP800 displays no inhibitory activity against the closely related GHKL ATPase, topoisomerase II, and the structurally unrelated ATPase, Hsp70 at the concentration of 10 μM. NVP-BEP800 potently inhibits the proliferation of various tumor cell lines with GI50 values ranging from 38 nM in A375 to 1.05 μM in PC3, and primary human tumors with the mean IC50 of 0.75 μM and IC70 of 1.8 μM. NVP-BEP800 treatment at the concentration of five times the GI50 increases the percentage of G2-M phase in A2058 and A549 cells and sub-G1 phase in BT-474, HCT116, A2058 and A549 cells by 29.5%, 33.6%, 42.7%, 12.1%, 5.9% and 7.1%, respectively. NVP-BEP800 treatment causes Akt and ErbB2 dephosphorylation, ErbB2 degradation, and Hsp70 induction in a concentration-dependent manner in BT-474 cells with IC50 values of 218 nM, 39.5 nM, 137 nM and 207 nM, respectively. Kinase Assay: Recombinant Hsp90β, TAMRA-radicicol, or various concentrations of NVP-BEP800 is added in assay buffer (50 mM TRIS pH 7.4, 5 mM MgCl2, 150 mM KCl, and 0.1% CHAPS), mixed, and incubated at room temperature for 30 to 45 minutes prior to reading. The 2D-FIDA-based HTS assay based on confocal technologies monitors the decreased fluorescence polarization on displacement of the high affinity ligand TAMRA-radicicol from Hsp90β by NVP-BEP800. The concentration of NVP-BEP800 which inhibits Hsp90β by 50% is determined from the competition curve. Cell Assay: Cells (A375, PC3, A2058, A549, HCT116, BT-474, SKBr3, MCF-7, MDAMB-157, MDA-MB-231, MDA-MB-468, and BT20) are exposed to NVP-BEP800 for 24 hours. Cell proliferation is determined using either sulforhodamine B for adherent cells or MTS assay for suspension cells or those showing low adherence. Cell death is determined using a ToxiLight nondestructive cytotoxicity bioassay kit. Cell cycle progression is determined by RNase A/propidium iodide staining following fixation in 70% ethanol. Caspase-3/7 activity is determined using a homogeneous caspase activity kit. |
|---|---|
| In Vivo | Oral administration of NVP-BEP800 at 15 or 30 mg/kg/day for 15 days causes a dose-dependent reduction in B-Raf and Akt phosphorylation levels, and displays significant dose-dependent antitumor efficacy in the A375 melanoma xenograft model with the T/C values of 53% and 6% at the dose of 15 and 30 mg/kg/day, respectively, suggesting almost complete tumor inhibition at 30 mg/kg/day. Administration of NVP-BEP800 induces dose-dependent increase of Hsp90-p23 complex dissociation and reductions in the levels of steady-state ErbB2, phospho-Akt and phospho-S6, in BT-474 breast cancer xenografts, and exhibits significant antitumor activity with 38% tumor regression at dose of 30 mg/kg/day and a T/C of 36% at dose of 15 mg/kg/day. |
| Animal model | Female Harlan HsdNpa: Athymic Nude-nu mice injected s.c. with BT-474 or A375 cells |
| Formulation & Dosage | Dissolved in 0.5% methyl cellulose; 50 mg/kg; oral gavage |
| References | Mol Cancer Ther. 2010 Apr;9(4):906-19. |
