Highly Potent and Selective Deubiquitinating Enzyme Inhibitor

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.

Potential Commercial Applications: Competitive Advantages:
  • 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 Stage:
  • Early-stage
  • In vitro data available

Related Invention(s):


David Maloney (NCATS)  ➽ more inventions...

Andrew Rosenthal (NCATS)  ➽ more inventions...

Ajit Jadhav (NCATS)  ➽ more inventions...

Thomas Dexheimer (NCATS)  ➽ more inventions...

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Qin Liang

Zhihao Zhuang

Intellectual Property:
US Pat: 9,802,904 issued 2017-10-31
US Application No. 61/747,052 filed on 2012-12-28
PCT Application No. PCT/US2013/077804 filed on 2013-12-26

Liang Q, et al. PMID 24531842
Singhal S, et al. PMID 19007433
Reyes-Turcu FE, et al. PMID 19489724
Hussain S, et al. PMID 19448430
Oestergaard VH, et al. PMID 18082605
Kim JM, et al. PMID 19217432
Chen J, et al. PMID 22118673
Dexheimer TS, et al. PMID 25506968

Collaboration 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 lili.portilla@nih.gov or 301-217-2589, or Dr. Krishna Balakrishnan at balakrik@mail.nih.gov or 301-217-2336. A notice was published in the Federal Register on Tuesday, June 24, 2014 detailing this opportunity: https://www.federalregister.gov/documents/2014/06/24/2014-14719/national-center-for-advancing-translational-sciences-ncats-cooperative-research-and-development.

Licensing Contact:
Ami Gadhia,
Email: ami.gadhia@nih.gov
Phone: 301-827-7159

OTT Reference No: E-043-2013-0
Updated: Nov 18, 2015