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BBB-Permeable PROTACs: Where Do We Stand?

Serena Francisco1, Giulia Apprato1, Matteo Rossi Sebastiano1

  • 1Department of Molecular Biotechnology and Health Sciences, MedChemBeyond Lab, University of Torino, Piazza Nizza 44bis, 10126 Torino, Italy.

ACS Medicinal Chemistry Letters
|April 15, 2026
PubMed
Summary
This summary is machine-generated.

Developing central nervous system (CNS)-active Proteolysis Targeting Chimeras (PROTACs) faces blood-brain barrier (BBB) challenges. This review analyzes models and CNS-targeted degraders, revealing a need for improved design strategies.

Keywords:
Blood−Brain BarrierCentral Nervous SystemPROTACsPermeabilitybRo5

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Discovery

Background:

  • The blood-brain barrier (BBB) restricts the entry of therapeutic agents into the central nervous system (CNS).
  • Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic modality but face significant challenges in crossing the BBB for CNS applications.
  • Effective CNS drug delivery is crucial for treating neurological disorders.

Purpose of the Study:

  • To review the physiology of the blood-brain barrier (BBB).
  • To critically evaluate existing in silico, in vitro, and in vivo models for assessing CNS drug penetration.
  • To analyze CNS-targeted degraders and identify design strategies for improved brain penetration.

Main Methods:

  • Literature review of BBB physiology and brain penetration models.
  • Compilation and analysis of 30 published CNS-targeted PROTACs.
  • Critical evaluation of current predictive models for CNS drug delivery.

Main Results:

  • The BBB presents a significant hurdle for the development of CNS-active PROTACs.
  • Existing models for predicting brain penetration show variability and limitations.
  • Analysis of 30 CNS-targeted degraders reveals a lack of a consistent and effective design strategy.

Conclusions:

  • Overcoming BBB limitations is essential for advancing CNS-active PROTAC therapeutics.
  • Development of standardized and reliable models is needed to predict brain penetration.
  • Future CNS-targeted degrader programs require a more unified and rational design approach.