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Background: NVP-BEP800 binds to the N-terminal ATP-binding pocket of Hsp90. 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. In BT-474 cells and A375 cells, NVP-BEP800 causes the Hsp90-p23 dissociation and client protein degradation (ErbB2) as well as the reduction of client protein phosphorylation (phospho-Akt). Degradation of these oncogenic client proteins results in tumor cell growth arrest and death.
Biological Activity: NVP-BEP800 is an ATP-competitive inhibitor of Hsp90β, with an IC50 of 58 nM in a competitive binding fluorescence polarization assay. Exhibits >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 (average GI50 of 245 nM), and 46 primary human tumors, including small cell lung, mammary cancer and melanoma, with the mean IC50 of 0.75 µM and IC70 of 1.8 µM. Did not inhibit 20 different protein kinases at IC50 > 10 µM. average GI50 of 245nM. Additionally, treatment of NVP-BEP800 induces apoptosis in human breast cancer cell lines. The antitumor efficacy of NVP-BEP800 is also observed with a dose of 15 or 30 mg/kg/d in A375 xenograft-bearing mice as well as in BT-474 breast cancer xenografts.
CAS Number: 847559-80-2
Description: NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH(2)-terminal ATP-binding pocket of Hsp90. NVP-BEP800 (also known as VER-82576) is a novel ATP-competitive HSP90β inhibitor that binds to the NH(2)-terminal ATP-binding pocket of Heat shock protein 90 (Hsp90). NVP-BEP800 induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. 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.
Solubility: Soluble in DMSO
Storage Stability: Store at or below -20°C. Solid form is stable at least 12 months from date of receipt, when stored as directed. Do not store aqueous solutions for more than one day.
Target: Hsp90β
Biosafety Level: Not applicable (BSL-1)
References: Massey AJ, et al. Mol Cancer Ther. 2010 Apr;9(4):906-19.
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