Induced-proximity therapeutics for targeted protein and RNA degradation: An organic chemistry Perspective-A review

TL;DR

This review explores how organic chemistry principles shape the design of drugs that use induced proximity to selectively degrade proteins and RNA in cells.

Contribution

The paper provides a novel organic chemistry-focused perspective on degrader design principles and linker optimization for induced-proximity therapeutics.

Findings

Linker chemistry significantly impacts degradation efficiency and pharmacokinetics of degraders.

Modular synthetic strategies and ligand optimization are critical for improving therapeutic potential.

Stereochemical control and RNA-binder optimization present key design challenges for degrader development.

Abstract

Induced-proximity therapeutics have emerged as a transformative paradigm in chemical biology and drug discovery, enabling selective control of cellular processes beyond conventional inhibitors. Between 2020 and 2025, major progress has been achieved across five modalities: proteolysis-targeting chimeras (PROTACs), molecular glues, lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs) and related tethering strategies, and ribonuclease-targeting chimeras (RIBOTACs). Each exploits endogenous degradation or regulatory pathways using chemically engineered bifunctional or monofunctional small molecules, thereby expanding the druggable proteome and transcriptome. This review provides a comparative analysis of their underlying organic chemistry, design principles, and mechanistic diversity. We highlight structure activity relationships, linker optimization, and chemical motifs that govern induced proximity and degradation efficiency. Advances in ligand discovery, modular synthetic methodologies, and strategies to improve pharmacokinetics and tissue selectivity are emphasized. Schematic diagrams illustrate key mechanistic steps, offering a visual framework for comparing similarities and differences across approaches. While prior reviews have focused on mechanistic and pharmacological aspects, our perspective emphasizes synthetic strategies, linker chemistry, SAR studies, and ligand optimization principles that underpin each degrader class. We examine how advances in synthetic design, modular assembly, and chemical reprogramming of ligases or receptors have broadened therapeutic potential. By critically assessing strengths, limitations, and chemical challenges across modalities, we propose a unifying organic chemistry perspective that distinguishes induced-proximity strategies from conventional small-molecule inhibition and outlines future opportunities in degrader design.

Image 1

•Degrader modalities—including PROTACs, molecular glues, LYTACs, AUTACs/ATTECs, RIBOTACs, and emerging platforms such as DUBTACs and TransTACs—use induced proximity to modulate proteins, organelles, and RNA target.•Organic-chemistry design challenges, such as linker installation, stereochemical control, glycan conjugation, and RNA-binder optimization, critically shape degrader function and developability.•Linker class (rigid, flexible, cleavable, macrocyclic, polarity-masking) strongly influences ternary-complex formation, degradation efficiency, and pharmacokinetic behavior.

Degrader modalities—including PROTACs, molecular glues, LYTACs, AUTACs/ATTECs, RIBOTACs, and emerging platforms such as DUBTACs and TransTACs—use induced proximity to modulate proteins, organelles, and RNA target.

Organic-chemistry design challenges, such as linker installation, stereochemical control, glycan conjugation, and RNA-binder optimization, critically shape degrader function and developability.

Linker class (rigid, flexible, cleavable, macrocyclic, polarity-masking) strongly influences ternary-complex formation, degradation efficiency, and pharmacokinetic behavior.

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