Proteolysis-targeting chimeras in drug development: A safety perspective

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic modality.
• PROTACs leverage the ubiquitin-proteasome system (UPS) to induce targeted protein degradation.
• First-generation PROTACs are advancing into clinical trials for oncology.

Purpose of the Study:

• To review the theoretical safety risks associated with PROTAC technology.
• To provide mechanistic insights into these safety concerns using in vitro and non-clinical in vivo data.
• To discuss strategies for mitigating risks in next-generation PROTAC development.

Main Methods:

• Review of existing literature and preclinical data.
• Analysis of in vitro experimental findings.
• Evaluation of non-clinical in vivo study results.

Main Results:

• Identified key safety risks: off-target degradation, E3 ligase substrate accumulation, proteasome saturation, and the hook effect.
• Mechanistic understanding of these risks derived from experimental data.
• Outlined approaches to mitigate identified safety liabilities.

Conclusions:

• Understanding and addressing PROTAC-related safety risks is crucial for therapeutic advancement.
• Next-generation PROTAC design incorporates strategies to enhance safety profiles.
• Mitigation efforts aim to broaden the therapeutic applications of PROTACs beyond oncology.