Identification and application of NEDD8 E1 inhibitors
Frank J Bruzzese1, Michael A Milhollen, James M Gavin
1Discovery, Millennium Pharmaceuticals Inc., Cambridge, MA, USA.
Methods in Molecular Biology (Clifton, N.J.)
|February 22, 2012
Summary
This study introduces a new assay to find inhibitors of the NEDD8 activating enzyme (NAE), crucial for cancer cell survival. This research supports the development of novel cancer therapeutics targeting the NEDD8 conjugation pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The NEDD8 conjugation pathway, initiated by NEDD8 activating enzyme (NAE), regulates cullin RING ligase (CRL) activity.
- CRL ligases control the turnover of substrates vital for cancer cell growth and survival via the ubiquitin proteasome system (UPS).
Purpose of the Study:
- To describe a biochemical and cell-based assay for identifying NAE inhibitors.
- To monitor the inhibition of the NEDD8 conjugation pathway by NAE inhibitors.
Main Methods:
- Development of a biochemical assay to screen for NAE inhibitors.
- Establishment of a cell-based assay to assess NAE inhibition in a cellular context.
Main Results:
- The described assays effectively identify inhibitors of NAE.
- These assays can monitor the functional inhibition of the NEDD8 conjugation pathway.
Conclusions:
- The developed assays are valuable tools for discovering and validating NAE inhibitors.
- This work supports the clinical development of NAE inhibitors as a novel cancer therapy.
