MLN4924: A novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy

Steffan T. Nawrocki, Patrick Griffin, Kevin R. Kelly, Jennifer S. Carew

Research output: Contribution to journalReview articlepeer-review

108 Scopus citations

Abstract

Introduction: The small ubiquitin-like molecule NEDD8 has been identified as an essential regulator of the activity of the cullin-RING E3 ubiquitin ligases (CRLs), which control the turnover of multiple proteins with fundamental roles in cancer biology. The aberrant function of the NEDD8 cascade within the context of malignancy makes it an attractive target for the development of novel anticancer agents. MLN4924 is a first-in-class inhibitor of the proximal regulator of the NEDD8 system (NEDD8-activating enzyme, NAE) that has entered Phase-I trials for cancer therapy and has established that significant therapeutic benefit can be achieved by antagonizing NEDD8-mediated protein degradation. Areas covered: This review provides a detailed overview of the NEDD8 system and discusses the mechanisms of action of MLN4924, a novel small molecule NAE inhibitor. Key findings from preclinical investigations of MLN4924 in a broad range of cancer models and preliminary findings from ongoing Phase-I clinical trials with MLN4924 are also discussed. Expert opinion: Targeting protein NEDDylation represents an exciting new anticancer strategy with demonstrable therapeutic benefit. Ongoing and future studies focused on dissecting the functional status/regulation of the NEDD8 system in individual tumor types will facilitate the design of novel approaches that yield optimal therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)1563-1573
Number of pages11
JournalExpert Opinion on Investigational Drugs
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2012

Keywords

  • Cancer
  • MLN4924
  • NEDD8
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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