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Advanced Neurology Brain bioavailability of targeted protein degraders

Table 5. Challenges associated with the ADME profiling of targeted protein degraders and major mechanisms of elimination
Most significant ADME/physicochemical Main challenges faced with measuring Major mechanisms of TPD elimination
property challenges facing the development of PPB of TPD
orally bioavailable (>30% F) degraders
Primary Secondary Metabolism Other pathways
Permeability P-gp Non-specific binding and poor recovery Pathways Biliary elimination
Solubility Metabolism/stability Analytical sensitivity limitations CYP450 Renal elimination
MW >3 HBDs and HBAs Solubility limitations Amidase Intestinal secretion
IVIVC Polarity/lipophilicity Equilibrium issues Esterase P-gp efflux
PPB Slow binding kinetics UGT OATP uptake
Absorption Plasma instability Hydrolysis
Aldehyde oxidase
GST
Abbreviations: ADME: Absorption, distribution, metabolism, and excretion; CYP450: Cytochrome P450; F: Oral bioavailability; GST: Glutathione
S-transferase; HBA: Hydrogen bond acceptors; HBD: Hydrogen bond donors; IVIVC: In vitro in vivo correlation; MW: Molecular weight; OATP:
Organic anion transporting polypeptide; P-gp: P-glycoprotein; PPB: Plasma protein binding; TPD: Targeted protein degraders;
UGT: UDP-glucuronosyltransferase.

compounds through optimal lipidation of the polar
parent molecule. While increasing lipophilicity enhances
drug delivery to the brain, this may not always translate
into increased efficacy. A plausible explanation is that
increased lipophilicity can lead to enhanced binding to
brain tissue, which in turn reduces the amount of free
drug available to interact with its therapeutic target within
the brain parenchyma. This consequence may also
155
Figure 5. XL01126 chemical structure affect properties, such as low aqueous solubility, rapid
metabolism, and cellular quenching. 156
even with low exposure, leading to amelioration of disease Water: octanol partition coefficient does not appear
conditions and symptomatic relief. Despite very low CNS to be a reliable metric for predicting BBB permeability.
bioavailability, XL01126 selectively degrades more than Instead, the experimental polar surface area has shown
95% of pathological tau in the mouse brain 24-h after a relatively better correlation (data not shown) with BBB
parenteral administration, while sparing the WT tau. permeability.
Other tau-targeting TPDs have exhibited even lower BBB
permeability. 4,154 For CNS-targeted therapies, molecular weight alone
cannot be considered a major determinant of BBB
To treat CNS neuropathies, small-molecule drugs
must traverse the BBB. Achieving reasonable permeability permeability for TPDs. Instead, structural composition—
especially the linker—and malleability appear to compensate
necessitates careful optimization of druggability properties for the high molecular weight, with polar functional groups
while retaining the molecule’s potency to achieve sufficient (hydroxyl [-OH], amino [-NH , or carboxyl [-COOH])
2
CNS concentration for the desired therapeutic efficacy. In groups enhancing aqueous solubility. In addition, alkyl/aryl
the case of TPDs, the challenge is significantly amplified due groups or fluorine substitution adjacent to the -OH group
to their high molecular weight and structural composition. can confer lipophilic traits. Among the three components of
To create a TPD with reasonable BBB permeability, TPDs (POI, linker, and E3 ligase ligand), the POI is unique
medicinal chemistry efforts may focus on masking polar based on the targeted protein, and the E3 ligase ligand is
functional groups, which can be particularly difficult given selected according to the abundance of E3 ligases at the site
the size and composition of TPDs.
of action. Thus, identifying BBB-permeable linker motifs
There are three primary approaches to increase the represents an essential strategy for optimizing TPDs’ CNS
exposure of drugs in the brain: augmenting diffusion, druggability properties.
curtailing efflux, and engaging non-saturable career Incorporating flexible PEG linkers is a common
transport.
approach in TPD designing. However, PEG linker’s
Many CNS-targeted drug discovery studies have exhibit low solubility, poor permeability, and poor plasma,
attempted to enhance the CNS delivery of hydrophilic chemical, and metabolic stability due to the presence

Volume 4 Issue 2 (2025) 68 doi: 10.36922/an.5140