E3 ligase ligand optimization of Clinical PROTACs

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic strategy for previously undruggable targets.
• The development of PROTACs relies on E3 ubiquitin ligase ligands, with limited options like VHL, CRBN, MDM2, and IAP currently utilized.
• Most PROTACs in clinical trials use Cereblon (CRBN) ligands, highlighting a need for broader ligand development.

Purpose of the Study:

• To review the structural optimization of E3 ligase ligands used in PROTACs entering clinical trials.
• To summarize the druggability characteristics of these ligands.
• To provide insights for developing more druggable PROTAC molecules.

Main Methods:

• Literature review of PROTACs and their E3 ligase ligands in clinical development.
• Analysis of structural modifications and optimization strategies for selected E3 ligase ligands.
• Evaluation of ligand druggability and therapeutic potential.

Main Results:

• Limited E3 ligase ligands (VHL, CRBN, MDM2, IAP) are currently employed in PROTAC development.
• CRBN-based ligands dominate PROTACs in clinical trials; VHL-based DT2216 is an exception.
• Structural optimization of E3 ligase ligands is critical for translating PROTAC technology from research to clinical application.

Conclusions:

• Structural optimization of E3 ligase ligands is paramount for the success of PROTAC technology.
• Enhancing ligand druggability is key to expanding the clinical utility of PROTACs.
• This review offers insights to guide medicinal chemists in developing novel, druggable PROTAC molecules.