Description of Invention:
Functional Hsp90 requires C-terminal homodimerization of two molecules of Hsp90. Novobiocin competes with ATP for binding to the C-terminus and studies demonstrated that this binding results in degradation of Hsp90 protein through ubiquitination and ultimately transportation to proteosome for proteolysis. Twenty three analogs of novobiocin were prepared and screened for their activity against Hsp90 and the most active derivatives were identified. Novobiocin was previously identified as an inhibitor of type II topoisomerases and has been used clinically for more then a decade for the treatment of cancer. However recent studies have shown that novobiocin selectively inhibits the maturation of Hsp90 dependent proteins. In addition to its affect on Hsp90, novobiocin has been shown to reverse drug resistance and increase the intracellular concentration of topoisomerase II drugs such as Etoposide and tubulin binding drugs, such as Taxol, making cells more susceptible to chemotherapeutics and induction of apoptosis.
Inventors:
Leonard M. Neckers (NCI) et al.
Patent Status:
DHHS Reference No. E-065-2005/0 --
U.S. Provisional Application No. 60/624,566 filed 03 Nov 2004
Relevant Publication:
This research is described, in part, in: Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B and Blagg BSJ. "Hsp90 Inhibitors Identified from a Library of Novobiocin Analogues," J. Am. Chem. Soc. (Communications) 2005 127 (37): 12778-12779; doi 10.1021/ja0535864 S0002-7863(05)03586-9.
Licensing Status:
In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.
Portfolios: Cancer
Cancer -Therapeutics-Biological Response Modifiers-Other Cancer -Therapeutics
For Additional Information Please Contact: Adaku Nwachukwu J.D.
NIH Office of Technology Transfer
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Rockville, MD 20852-3804
Phone: 301 435-5560
Email: madua@mail.nih.gov
Fax: 301 402-0220
