Massey, A. J., Schoepfer, Joseph, Brough, P. A., Brueggen, Josef, Chene, Patrick, Drysdale, M. J., Pfaar, Ulrike, Radimerski, Thomas, Ruetz, Stephan, Schweitzer, Alain, Wood, M, Garcia-Echeverria, Carlos and Jensen, Michael Rugaard (2010) Preclinical anti-tumor activity of the orally available Hsp90 inhibitor NVP-BEP800. Molecular cancer therapeutics, 9 (4). pp. 906-919.

Abstract

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. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor which binds to the N-terminal ATP-binding pocket of Hsp90. NVP-BEP800 demonstrated activity against 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-RafV600E, Raf-1 and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well-tolerated and induced robust anti-tumor 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 anti-tumor activity. NVP-BEP800 demonstrated 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. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development.

Item Type:	Article
Keywords:	Hsp90, Chaperone, BEP800
Date Deposited:	13 Oct 2015 13:17
Last Modified:	13 Oct 2015 13:17
URI:	https://oak.novartis.com/id/eprint/1161