Bifunctional proximity-inducing strategies for targeted and programmable post-translational modifications.

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Proteolysis-targeting chimeras (PROTACs) represent a significant advancement in targeted protein degradation.
• Classical PROTACs primarily utilize the ubiquitin-proteasome system for degrading target proteins.
• Limitations in E3 ligase diversity and context-dependent efficacy necessitate further innovation.

Purpose of the Study:

• To review the evolution of PROTAC technology from its inception to its current status as a versatile platform for proximity-driven protein regulation.
• To explore emerging PROTAC architectures and related proximity-based modalities.
• To discuss the expansion of targeted protein degradation beyond mammalian systems.

Main Methods:

• Review of scientific literature on PROTACs and related proximity-based technologies.
• Analysis of design principles and mechanistic underpinnings of various PROTAC architectures.
• Examination of novel approaches to expand E3 ligase repertoires and target previously inaccessible biomolecules.

Main Results:

• PROTACs have evolved to engage lysosomal, autophagic, and organelle-directed clearance pathways.
• Novel strategies are addressing limitations by exploring new E3 ligases and employing AI-guided design.
• Proximity-based modalities like LYTACs, AUTACs, RIBOTACs, and functional modulation techniques (DUBTACs, PHICS, etc.) are expanding the scope of proximity pharmacology.
• Bacterial PROTACs (BacPROTACs) demonstrate the cross-domain applicability of this technology.

Conclusions:

• The field is transitioning from degradation-centric PROTACs to a comprehensive proximity pharmacology framework.
• This broader framework enables precise control over protein fate, function, and therapeutic tractability.
• Targeted protein degradation and induced proximity are reshaping molecular biology and drug discovery.