Technology ID
TAB-4483
A New Molecular Scaffold for Targeting hRpn13 as a Treatment for Cancer
E-Numbers
E-056-2021-0
Lead Inventor
Sabbasani, Venkatareddy (NHLBI)
Co-Inventors
Walters, Kylie (National Cancer Institute (NCI))
Lu, Xiuxiu (Structural Biophysics Laboratory)
Tarasova, Nadya (Cancer Innovation Laboratory)
Swenson, Rolf (NHLBI)
Applications
Therapeutics
Therapeutic Areas
Oncology
Development Stages
Pre-clinical (in vivo)
Lead IC
NHLBI
ICs
NHLBI
This technology includes a new chemical scaffold (with lead compound XL5) against hRpn13 that induces apoptosis, which may have clinical efficacy against cancer. The structure of XL5-conjugated hRpn13 guided the design of XL5-PROTAC degrader compounds that exhibit greater efficacy than previous hRpn13-targeting compounds, as evaluated by selectivity for hRpn13, induction of apoptosis, and loss of cell viability. In cells, XL5-PROTACs revealed the presence of a truncated hRpn13 product that binds to proteasomes and is selectively degraded by XL5-PROTACs. The presence of this truncated hRpn13 protein correlates with induction of apoptosis by XL5-PROTACs, providing a previously unknown mechanism of action for hRpn13 targeting.
Commercial Applications
In the near term, this chemical scaffold against hRpn13 can be used to 1) interrogate hRpn13 function in cells and 2) further development of hRpn13-targeting molecules for clinical application. In the long-term, this chemical scaffold and derived PROTACs or AUTACs may be clinically effective.
Competitive Advantages
A next generation of hRpn13-targeting molecules that include degraders has been generated with superior efficacy compared to all previous generation molecules. These reagents and the structure-function assays provide insights into further optimization possibilities and set the stage for clinical trials. Moreover, the mechanism of action for hRpn13 targeting has now been revealed by using these molecules and defined to be a previously unknown Rpn13 species.
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