Targeting cullin neddylation for cancer and fibrotic diseases

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Biology
• Drug Discovery

Background:

• Protein neddylation is a critical post-translational modification.
• Cullin-RING ligases (CRLs), central to neddylation, are often dysregulated in cancers and fibrotic diseases.
• Targeting the neddylation pathway presents a novel therapeutic strategy.

Purpose of the Study:

• To systematically review the enzymes involved in protein neddylation.
• To highlight advancements in the medicinal chemistry of neddylation inhibitors.
• To discuss the therapeutic potential of targeting neddylation for cancer and fibrotic diseases.

Main Methods:

• Literature review of neddylation pathway enzymes and inhibitors.
• Analysis of structural and functional data of key neddylation enzymes.
• Review of medicinal chemistry efforts in developing neddylation inhibitors.
• Examination of clinical trial data for approved neddylation inhibitors.

Main Results:

• Neddylation pathway proteins are frequently overactivated in various cancers and fibrotic conditions.
• MLN4924, a prominent neddylation inhibitor, is in clinical trials for multiple cancers.
• Significant progress has been made in developing small molecule inhibitors targeting neddylation.

Conclusions:

• Targeting protein neddylation is a promising therapeutic avenue for cancer and fibrotic diseases.
• Continued research into neddylation inhibitors may yield effective treatments.
• Understanding neddylation enzyme structures and functions is key to inhibitor development.