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

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.

• Authors: Steffan T Nawrocki, Patrick Griffin, Kevin R Kelly, Jennifer S Carew
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 21 Issue 10 Pg. 1563-73 (Oct 2012) ISSN: 1744-7658 [Electronic] England
• PMID: 22799561 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Cyclopentanes
• NEDD8 Protein
• NEDD8 protein, human
• Pyrimidines
• Ubiquitins
• pevonedistat

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cyclopentanes (pharmacology, therapeutic use)
• Humans
• NEDD8 Protein
• Neoplasms (drug therapy, metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• Ubiquitins (antagonists & inhibitors)