Artificial intelligence empowers targeted protein degradation: Core technological innovations, multi‐scenario applications, and translational prospects

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

This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.

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.

Emerging Trends in Artificial Intelligence-Driven Drug Discovery: Balancing Chemical Design and Pharmacological Properties for Cancer Therapy.

This review emphasizes the influence of new AI platforms like AlphaFold3, molecular interactions are structurally optimized (MISATO), and ZairaChem on the discovery of oncology drugs and examines how AI reconciles chemical design with pharmacological feasibility.

Post-translational chemical modification of E3 ligase for efficient target protein degradation.

Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy, with proteolysis-targeting chimeras (PROTACs) leading efforts to address previously undruggable targets. However, PROTACs face challenges such as low bioavailability and poor pharmacokinetic properties which limit their biological applications. Here, we report a strategy termed post-translational chemical modification targeting chimera (PTcM-TAC), which integrates ligand-directed chemistry into the PROTAC framework to achieve sustained target protein degradation through covalent modification of E3 ligases. PTcM-TAC incorporates an electrophilic dibromophenyl benzoate warhead into the linker connecting the E3 ligase ligand and the protein-of-interest (POI) ligand, enabling selective transfer of the POI ligand onto the recruited E3 ligase while releasing the E3-binding moiety. Mechanistic studies, including LC-MS/MS peptide mapping, pull-down assays, and structural modeling, demonstrated site-selective modification of CRBN by the PTcM-TAC. The resulting ligand-labeled E3 ligase enables sustained pseudo-catalytic target recognition through a simplified binary interaction, thereby maintaining degradation activity even after compound washout. Furthermore, we successfully applied the PTcM-TAC strategy to another representative E3 ligase, von Hippel-Lindau (VHL), which exhibited substantially sustained degradation activity compared with conventional PROTACs. To our knowledge, PTcM-TAC represents the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase. We believe that PTcM-TAC could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.

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.