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Highly Potent and Selective Deubiquitinating Enzyme Inhibitor

Posted Apr 03 2013 8:00pm

Description of Invention:
Available for licensing are inhibitors that target the USP1/ UAF1 deubiquitinating enzyme (DUB) complex. The FDA approval and commercial success of Velcade®, a small molecule proteasome inhibitor, has established the ubiquitin-proteasome system (UPS) as a valid target for anticancer treatment. However, proteasome inhibitors in general suffer from a narrow therapeutic index and acquired resistance. A promising alternative to proteasome inhibition has been to target the enzymes upstream of proteasome-mediated protein degradation, i.e. the ubiquitin conjugation and deconjugation, to generate more specific, less toxic therapeutic agents. The investigators have developed small molecules that target the USP1/ UAF1 DUB complex that acts upstream of UPS and has been implicated in the DNA damage response. These compounds are the most potent and selective DUB inhibitors reported to date. Moreover, the inhibitors act synergistically with cisplatin, a DNA damaging anti-cancer drug, to overcome chemoresistance and enhance cytotoxicity. These results suggest the inhibitors may also improve the efficacy and potency of other commonly prescribed chemotherapeutic agents that are known to induce DNA damage.

  • Method to treat cancer
  • Method to overcome chemoresistance to cisplatin
  • Pharmaceutical compositions

  • Represents the most potent and selective DUB inhibitor reported to date.
  • Promising alternative to proteasome inhibition offering the potential of more selective and less toxic therapeutic agents.
  • Acts synergistically with DNA damaging agents to overcome chemoresistance.

Development Status:
  • Early-stage
  • In vitro data available

David J Maloney (NCATS)
Andrew Rosenthal (NCATS)
Ajit P Jadhav (NCATS)
Thomas S Dexheimer (NCATS)
Anton M Simeonov (NCATS)
Qin Liang (University of Delaware)
Zhihao Zhuang (University of Delaware)

Patent Status:
HHS, Reference No. E-043-2013/0
US, Application No. 61/747,052 filed 28 Dec 2012

Related Technologies:
US, Application No. 12/669,361 filed 15 Jan 2010, Reference No. E-208-2007/0
US, Application No. 61/692,560 filed 23 Aug 2012, Reference No. E-156-2012/0
US, Patent No. 7,498,336, Issued 03 Mar 2009, Reference No. E-231-2002/0
US, Patent No. 8,242,160, Issued 14 Jun 2012, Reference No. E-070-2005/0
US, Application No. 13/547,417 filed 12 Jul 2012, Reference No. E-070-2005/0
US, Application No. 60/447,610 filed 13 Feb 2003, Reference No. E-231-2002/0
US, Application No. 60/738,242 filed 19 Nov 2005, Reference No. E-070-2005/0
US, Application No. 60/961,202 filed 18 Jul 2007, Reference No. E-208-2007/0

Collaborative Research Opportunity:
The National Center for Advancing Translational Sciences is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize this invention. For collaboration opportunities, please contact Lili Portilla at .

For Licensing Information Please Contact:
Jennifer Wong
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4633
Fax: 301-402-0220

Ref No: 2545

Updated: 04/2013

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