AI Article Synopsis
- The development of inhibitors targeting the ubiquitin-proteasome system has potential for treating human cancers.
- NEDD8-activating enzyme (NAE) plays a crucial role in regulating protein turnover via cullin-RING ligases, influencing cancer cell growth.
- MLN4924 is a potent NAE inhibitor that induces cancer cell death by disrupting protein turnover and affects DNA synthesis, showing promise in reducing tumor growth in animal models.
Article Abstract
The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
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