Bioorthogonal Chemistry: An Emerging Strategy for Targeted Protein Degradation

ABSTRACT Targeted protein degradation (TPD) technologies represent a promising strategy to overcome drug resistance associated with traditional small‐molecule inhibitors (SMIs) while targeting traditionally considered nondruggable targets. However, the frequent noncompliance of TPD agents with Lipinski's “Rule of Five” poses significant druggability challenges. Off‐target toxicity and the “hook effect” further limit TPD applications. With the development of bioorthogonal chemistry, self‐assembly TPD agents and TPD agent prodrugs based on bioorthogonal chemistry offer a viable solution to address these issues. This review summarizes recent advances in integrating bioorthogonal chemistry with TPD technologies, specifically highlighting its role in improving conventional TPD agents drawbacks.