1. Academic Validation
  2. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

  • Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884.
Teresa A Soucy 1 Peter G Smith Michael A Milhollen Allison J Berger James M Gavin Sharmila Adhikari James E Brownell Kristine E Burke David P Cardin Stephen Critchley Courtney A Cullis Amanda Doucette James J Garnsey Jeffrey L Gaulin Rachel E Gershman Anna R Lublinsky Alice McDonald Hirotake Mizutani Usha Narayanan Edward J Olhava Stephane Peluso Mansoureh Rezaei Michael D Sintchak Tina Talreja Michael P Thomas Tary Traore Stepan Vyskocil Gabriel S Weatherhead Jie Yu Julie Zhang Lawrence R Dick Christopher F Claiborne Mark Rolfe Joseph B Bolen Steven P Langston
Affiliations

Affiliation

  • 1 Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. [email protected]
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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