Deubiquitinating enzymes as therapeutic targets in cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The ubiquitin-proteasome system (UPS) plays a critical role in cellular protein homeostasis and is implicated in various human diseases.
• While proteasome inhibitors like Bortezomib are clinically used, targeted inhibition of deubiquitinating enzymes (DUBs), a key component of the UPS, remains an unmet clinical need.
• DUBs are emerging as crucial regulators within the UPS, making them attractive targets for therapeutic intervention.

Purpose of the Study:

• To review the current knowledge on deubiquitinating enzymes (DUBs), including their structures, substrates, and known small inhibitor molecules.
• To provide a comprehensive overview that can guide the rational design and development of novel, specific small molecule inhibitors targeting DUBs for cancer therapy.
• To highlight the importance of understanding DUB molecular mechanisms for advancing therapeutic strategies.

Main Methods:

• Literature review of published studies on deubiquitinating enzymes (DUBs).
• Analysis of structural information, substrate specificities, and identified small inhibitor molecules for various DUBs.
• Synthesis of current findings to establish a rationale for future drug development.

Main Results:

• The review consolidates information on the structures and substrates of identified DUBs.
• It summarizes the landscape of existing small inhibitor molecules targeting DUBs.
• The study identifies gaps in understanding the molecular mechanisms of DUB inhibitors.

Conclusions:

• Deubiquitinating enzymes (DUBs) represent a promising class of targets for novel cancer therapeutics.
• Further research into DUB structures and substrate specificities is essential for developing effective and specific small molecule inhibitors.
• This review provides a foundation for the rational design of DUB-targeted drugs to combat cancer.