TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

Targeted protein degradation: mechanistic diversity, therapeutic expansion, and clinical translation.

Targeted protein degradation (TPD) has transitioned from a paradigm-shifting concept to a clinically validated strategy, with multiple degraders achieving proof-of-concept in oncology and a rapidly expanding toolbox. By co-opting the ubiquitin-proteasome system to eliminate pathogenic proteins in an event-driven manner, TPD addresses targets long deemed undruggable. To capture this momentum, we present a comprehensive overview of the field. We dissect the mechanisms of heterobifunctional PROTACs and their clinical translation, covering late-stage programs targeting canonical oncogenic drivers (AR, ER, BTK) and emerging first-in-human studies against historically challenging targets such as STAT3 to illustrate both clinical validation and mechanistic expansion. Beyond classical PROTACs, we systematically summarize the expanding TPD toolbox: lysosome-targeting chimeras for degrading extracellular and membrane proteins, autophagy-based degraders for clearing aggregates and damaged organelles, antibody- and nucleic acid-derived PROTAC formats for tissue-specific delivery and transcription factor targeting, deubiquitinase-targeting chimeras for protein stabilization, and proximity-based post-translational modification editing, collectively demonstrating the broad reach of proximity-inducing pharmacology. By integrating molecular mechanisms with therapeutic applications, this review illustrates how TPD is reshaping the druggable proteome. We outline key challenges including novel E3 ligase ligand discovery, tissue selectivity, and acquired resistance, and discuss how covalent fragment screening, artificial intelligence, and expanded E3 ligase repertoires will advance next-generation degraders to fulfill the promise of event-driven pharmacology. This review provides a roadmap for translating TPD into transformative therapies.

[Development of Protein and RNA Degraders for Drug Discovery].

Targeted protein degradation (TPD) is an emerging approach that selectively eliminates specific proteins using synthetic molecules, such as proteolysis-targeting chimeras (PROTACs). It has attracted increasing attention in medicinal chemistry and chemical biology, with several PROTACs being tested in clinical settings. Unlike traditional small molecules, such as enzyme inhibitors and receptor antagonists, PROTACs exhibit a fundamentally different mechanism. Conventional drugs block enzymatic activities or receptor interactions, whereas PROTACs induce the degradation of target proteins, decreasing their cellular levels and abolishing all associated functions. PROTACs targeting enzymes in protein complexes disrupt both their catalytic activity and involvement in complex formation. In some cases, they also degrade other proteins in complexes, facilitating the elimination of entire assemblies. Our study leverages these unique features of TPD. We are currently developing various PROTACs targeting the enzymes responsible for lysine acetylation or methylation in proteins. Recently, the TPD concept has been extended beyond proteins to include nucleic acids, and ribonuclease-targeting chimeras (RIBOTACs) that selectively degrade RNA have been developed. We are also actively exploring new RNA-targeted degradation strategies. Herein, we highlight our recent work on TPD-inducing small molecules and provide an overview of RIBOTACs, which represent an area of growing research interest.

Advances in the Application of PROTAC Technology in Cancer Therapy

Traditional small-molecule anticancer inhibitors primarily block single protein activities and are vulnerable to mutation-mediated drug resistance. Proteolysis-targeting chimera (PROTAC) technology induces the ubiquitin-proteasome-dependent clearance of oncogenic proteins and provides a promising new strategy for precision cancer therapy. This paper summarizes the molecular basis, degradation mechanism, design principles, and translational progress of PROTAC degraders in cancer treatment. PROTACs consist of a target ligand, an E3 ubiquitin ligase ligand and a connecting linker, and they exert unique event-driven antitumor effects by inducing ternary complex formation and target ubiquitination. Representative ER, AR, BTK, BCL-xL, and BRD4 degraders have shown promising preclinical or clinical activity, especially in drug-resistant tumors. Current challenges include poor oral pharmacokinetic properties, incomplete tumor selectivity, uncertain long-term safety, and emerging resistance mechanisms related to ubiquitin signaling. Optimized ligand-linker design, tumor-selective E3 ligases, prodrug strategies and biomarker-guided clinical trials are expected to greatly promote the clinical development of PROTAC-based anticancer therapies.

PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy to eliminate pathogenic proteins that are difficult to modulate with traditional occupancy-based inhibitors. However, their clinical translation is often limited by poor aqueous solubility, suboptimal cellular permeability, and off-target effects. Notably, some PROTACs retain potent biological activity despite limited membrane permeability, owing to their catalytic mechanism of action, which allows even a small number of molecules reaching the target site to drive substantial protein degradation and produce important pharmacological effects. Growing evidence supports the application of PROTAC-based approaches in neurodegenerative diseases, where the selective removal of toxic or misfolded proteins is particularly attractive. This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.

Targeted protein degradation: bridging chemical biology and clinical translation.

Leveraging peptides for targeted protein degradation.

OBJECTIVES Targeted protein degradation (TPD) technology, with a particular emphasis on proteolysis-targeting chimeras (PROTAC), has emerged as a pivotal advancement in the field of drug discovery. However, several challenges-including the identification of suitable ligands for traditionally undruggable proteins, issues related to poor solubility and permeability, nonspecific biodistribution, and off-target toxicity-have significantly hindered their clinical translation. Peptides, recognized for their ability to serve as promising ligands for broad molecular recognition, exhibit unique potential to address these limitations in TPD applications. METHODS Literature and related information were collected from online resources such as Google Scholar, Web of Science, PubMed, CNKI, Baidu Scholar, and X-mol. KEY FINDINGS Recent advancements in peptide-mediated TPD have shown promise in overcoming these challenges as researchers focus on engineering highly selective peptides that enhance binding affinity for traditionally undruggable proteins while optimizing their solubility and permeability, with next-generation delivery systems also developed to reduce nonspecific biodistribution and off-target toxicity, thereby improving the therapeutic potential of peptide-based TPD approaches. CONCLUSIONS This review summarizes recent advancements in peptide-based PROTAC development, focusing on innovative delivery strategies and methods for enhancing efficiency, while also offering insights into future prospects aimed at optimizing therapeutic precision and efficacy.