Rosenthal, Andrew (NCATS)
Jadhav, Ajit (NCATS)
Dexheimer, Thomas (NCATS)
Simeonov, Anton (NCATS)
Liang, Qin (University of Delaware)
Zhuang, Zhihao (University of Delaware)
- In vitro data available
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.