An overview of the developmental trajectory of the TPD field is provided and how diverse modalities can be leveraged to address intracellular, membrane-associated, and extracellular protein targets are discussed.
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.
Caiyu Wang, Zhibin Guo, Yufei Liu et al.· International journal of pha...· 0 citations
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.
N. Vijaya Lakshmi Reddy, M. Sarika, V. Deepika et al.· International Journal of Adv...· 0 citations
The structural and medicinal chemistry principles underlying (i) allosteric inhibition and (ii) proximity-induced degradation are summarized, with an emphasis on design logic, structure-activity relationships, and key liabilities in the beyond rule of five space.
Mei Zhou, Linshan Li, Xiaojuan Tang et al.· Future Medicinal Chemistry· 0 citations
This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.
Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio et al.· Pharmaceuticals· 0 citations
The core mechanisms of Nano-TPD, encompassing targeted delivery, intracellular trafficking, stimuli-triggered release, and enhanced protein degradation via UPS or lysosomal pathways, are systematically elaborated.
Miaoxizi Luo, Jiaqi Ma, Chuan Hu et al.· The Innovation Drug Discover...· 0 citations
This work reports 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, and believes it could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.
Eunbin Park, Jinjoo Jung, Gangasani Jagadeesh Kumar et al.· Bioorganic chemistry (Print)· 0 citations
