Description of Invention:
This invention is directed to depletion of the Heat Shock Protein (HSP)-90 with novobiocin. Hsp90 is an essential and abundant chaperone in eukaryotes. It is considered today an exciting molecular target for cancer therapy. NIH inventors demonstrated previously that the gyrase-B inhibitor, novobiocin, and its related coumarin derivatives interact with Hsp90, causing in vitro and in vivo depletion of key regulatory Hsp90-dependent proteins. Using deletion/mutation analysis, the inventors have identified the novobiocin binding domain on Hsp90 and demonstrated that it overlaps a functional ATP binding site, which was previously unknown. These results identify a second site on Hsp90 where the binding of small molecule inhibitors can significantly impact this chaperone’s function, and thus support the hypothesis that both N- and C-terminal domains of Hsp90 interact to modulate chaperone activity. The inventors have performed preliminary in vivo experiments, treating mice carrying tumor xenografts with novobiocin encapsulated in Alzet pumps (slow, constant release for one month). The treated mice exhibited significantly slower tumor growth. Results of these studies demonstrated a significantly slower growth of tumors.
Inventors:
Monica G. Marcu (NCI) Leonard M. Neckers (NCI) Theodor W. Schulte (NCI)
Patent Status:
DHHS Reference No. E-084-1999/0 --
U.S. Patent Application No. 09/936,449, with priority to 12 Mar 1999
Portfolios: Cancer
Cancer -Therapeutics
For Additional Information Please Contact: Adaku Nwachukwu J.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301 435-5560
Email: madua@mail.nih.gov
Fax: 301 402-0220
