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Advanced Neurology Brain bioavailability of targeted protein degraders

polar hydrophilic compounds, or efflux transporter crosses BBB. It also discusses the physiochemical properties
substrates exhibit poor BBB permeability. Despite these of TPDs that may regulate their CNS bioavailability.
well-established metrics for CNS drug candidates, drug Furthermore, the best approaches to assess the BBB
development for CNS indications remains challenging, permeability of TPDs are discussed, along with their
as evidenced by the fact that only approximately 350 importance. Finally, the review explores the mechanism of
drugs out of over 7,000 in comprehensive medicinal CNS bioavailability driven by BBB disruption rather than
chemistry databases have been approved to treat CNS by BBB permeability.
diseases. Furthermore, among this 5%, many CNS active
3
agents, including antimigraine drugs, narcotic analgesics, 2. The complex organ: Brain
mood elevators/antidepressants, sedatives, tranquilizers, The brain regulates thoughts, emotions, memory, sensory
and hypnotics, exhibit poor pharmacokinetic/ and motor functions, vision, lung functioning, temperature,
pharmacodynamic (PK/PD) correlations.
satiety, and the body’s homeostasis mechanisms. Together
For targeted protein degraders (TPDs), achieving good with the spinal cord, it constitutes the CNS. The adult brain
BBB permeation efficiency is even more challenging due to is approximately 60% lipid, which includes phospholipids
their higher molecular weight (800 – 1,200 Da), increased such as phosphatidylcholine, phosphatidylethanolamine,
number of HBAs, HBDs, and rotatable bonds. Despite omega-3 fatty acid (docosahexaenoic acid, alpha-linolenic
these obstacles, several TPDs in preclinical settings have acid, and eicosapentaenoic acid), while the remaining 40%
demonstrated quantifiable concentrations in cerebrospinal consists of water, carbohydrates, proteins, and minerals.
fluid (CSF) and the brain, and are being developed for CNS The brain is composed of two distinct regions: white matter
indications. A few notable examples are listed in Table 1. (the lighter, inner core) and gray matter (the darker, outer

This review outlines the different routes that portion). In the spinal cord, however, the arrangement is
macromolecules (both chemical and biological) use to reversed, with white matter forming the outer portion,
cross the BBB and the likely mechanisms by which TPD consisting of axons (long fibers that connect neurons),

Table 1. Targeted protein degraders in development for central nervous system indications and their attributes

TPD ID Structure Indication and target Properties References
XL01126 Parkinson’s disease; tPSA: 194.3; Mol wt: 4
Leucine-rich repeat 1,019.7; XLogP: 5.05
kinase 2 degrader

QC-01-175 Alzheimer’s disease; tPSA: 171.82; Mol wt: 5
Degrader of pathogenic 626.25; XLogP: 0.98
tau protein

C004019 Alzheimer’s disease tPSA: 302.39; Mol wt: 6
selectively promotes 1,034.48; XLogP: 1.81
tau protein degradation

Abbreviations: CRBN: Cereblon; Mol. wt: Molecular weight; TPD: Targeted protein degraders; tPSA: Topological polar surface area; VHL: Von Hippel–
Lindau; XlogP: Prediction of octanol/water partition coefficient.

Volume 4 Issue 2 (2025) 55 doi: 10.36922/an.5140