PROTACs in Action: Bridging Chemical Biology and Drug Discovery for Protein Degradation

PROTACs enable targeted protein degradation via ubiquitin–proteasome system.
vent-driven pharmacology allows sustained effects with transient drug exposure.
Heterobifunctional design links target protein and E3 ligase for degradation.
AI and computational tools accelerate PROTAC design and optimization.
Clinical applications span oncology, autoimmune, and neurodegenerative diseases.

KEYWORDS

Machine learning

Protein degradation

PROTAC

E3 ubiquitination

Nano-PROTAC

TOPICS

ABSTRACT

Proteolysis-targeting chimeras (PROTACs) represent a transformative paradigm in drug discovery, fundamentally altering how we approach protein-targeted therapeutics by harnessing the ubiquitin-proteasome system for selective protein degradation. This comprehensive review examines the evolution of PROTAC technology from its conceptual origins in 2001 to its current clinical validation, with over 30 molecules in various stages of clinical development as of 2024. We explore the mechanistic foundations of PROTAC action, including the catalytic mode of protein degradation that distinguishes event-driven from occupancy-driven pharmacology, and examine the structural design principles governing heterobifunctional architecture, linker optimization, and E3 ligase recruitment strategies. The review analyzes current therapeutic applications across oncology, autoimmune diseases, and neurodegenerative disorders, highlighting the clinical success of compounds like ARV-471 and ARV-110 in Phase III trials. Critical challenges including physicochemical property optimization, resistance mechanisms, and bioavailability limitations are addressed alongside emerging solutions through computational design, artificial intelligence integration, and next-generation platforms including conditional degraders, nano-PROTACs, and expanded E3 ligase recruitment. Recent advances in molecular glue degraders, which represent 66% of FDA-approved degraders, and the development of precision medicine approaches through biomarker-guided therapy are also examined. The review concludes with an assessment of future directions, including E3 ligase repertoire expansion beyond the current focus on CRBN and VHL, targeting of previously undruggable proteins, and the integration of PROTAC technology with combination therapies and precision medicine strategies.

ABBREVIATIONS

PROTAC – Proteolysis-Targeting Chimera
UPS – Ubiquitin-Proteasome System
E1 – Ubiquitin-Activating Enzyme
E2 – Ubiquitin-Conjugating Enzyme
E3 – Ubiquitin Ligase
POI – Protein of Interest
Ub – Ubiquitin
CRBN – Cereblon
VHL – Von Hippel–Lindau
MDM2 – Mouse Double Minute 2
IAPs – Inhibitors of Apoptosis Proteins
PEG – Polyethylene Glycol
AI – Artificial Intelligence
ML – Machine Learning
MD – Molecular Dynamics
BTK – Bruton’s Tyrosine Kinase

ACKNOWLEDGEMENTS

The author thankfully acknowledge the Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720, Westview Drive SW, 30310, Atlanta, United States for providing necessary facilities for performing this study.

FUNDING

This research received no external funding. The study was conducted without any financial support from public, commercial, or not-for-profit funding agencies. All resources utilized for this work were provided by the author respective institutions.

CONFLICT OF INTEREST

The authors declare that there are no conflicts of interest regarding the publication of this article. The authors have no financial, commercial, or personal relationships that could have influenced the work reported in this manuscript.

PEER REVIEW INFORMATION

Article has been screened for originality

REFERENCES (96)

Abeje YE, Wieske LHE, Poongavanam V, Maassen S, Atilaw Y, Cromm P, Lehmann L, Erdelyi M, Meibom D, Kihlberg J. (2025), Impact of Linker Composition on VHL PROTAC Cell Permeability, J Med Chem, 68(1):638-657. doi:10.1021/acs.jmedchem.4c02492. PMID: 39693386.