Eeyarestatins: Novel Deubiquitination Inhibitors for the Treatment of Drug-Resistant Cancers

The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma.

The present invention for the first time describes that Eeyarestatins, a new class of small molecules, are potential anti-cancer agents. The compounds inhibit the deubiquitination of proteins by targeting the deubiquitination enzymes in the protein degradation pathway. More specifically, the inventors have demonstrated that the Eeyarestatins successfully kill different leukemia and lymphoma cell lines as well as leukemia cells isolated from patients with chronic lymphocytic leukemia by inducing the expression of Noxa, a pro-apoptotic member of the Bcl-2 protein family. Additionally, Eeyarestatins are active against cells that are resistant to Bortezomib and thus can be effective against drug-resistant tumors.

Potential Commercial Applications: Competitive Advantages:
  • Eeyarestatins can be developed for the treatment of deubiquitination related disorders such as cancers and proliferative disorders.
  • Eeyarestatins can potentially have broader use against HIV and immune related disorders considering the role of deubiquitination in budding of retroviruses and immune regulation.
  • Eeyarestatins are active against cells that are resistant to Bortezomib.
  • In vitro data shows activity of Eeyarestatins against primary cells from patients with chronic lymphocytic leukemia. Clinical trials show that Bortezomib is inactive against patients suffering from chronic lymphocytic leukemia.

Development Stage:
In vitro studies are completed and in vivo animal model studies are planned.


Adrian Wiestner (NHLBI)  ➽ more inventions...

Yihong Ye (NIDDK)  ➽ more inventions...

Qiuyan Wang (NIDDK)  ➽ more inventions...

Helena Mora-Jensen (NHLBI)  ➽ more inventions...

Intellectual Property:
U.S. Pat: 8,637,560 issued 2014-01-28
PCT Application No. PCT/US2008/08797
US Application No. 12/669,361

Q Wang, L Li, Y Ye. Inhibition of p97-dependent protein degradation by Eeyarestatin I. J Biol Chem. 2008 Jan 16; Epub ahead of print, doi 10.1074/jbc.M708347200. PubMed abs

Collaboration Opportunity:

The National Institutes of Health laboratories of Dr. Adrian Wiestner (NHLBI) and Dr. Yihong Ye (NIDDK) are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Eeyarestatins. Please contact Dr. Wiestner (301-594-6855, or Dr. Ye (301-594-0845, for more information.

Licensing Contact:
Michael Shmilovich, J.D.
Phone: 301-435-5019

OTT Reference No: E-208-2007-0
Updated: Jun 14, 2010