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Advanced Neurology Brain bioavailability of targeted protein degraders

machinery. To modify the optimal amount of POI molecular weight, electric charge, extent of plasma protein
degradation, dosing regimens may need to be adjusted, as binding, tPSA, number of rotatable bonds, HBDs, and
POIs with long half-lives will influence the duration of the HBAs. As the drug’s molecular weight increases, its ability
therapeutic effect. to traverse the BBB does not increase proportionally
with its lipophilicity. Moreover, as the drug’s surface area
16. BBB disruption-driven CNS increases from 52 Å (for a molecule with a molecular
bioavailability mass of 200 Da) to 105 Å (for a drug with a molecular
TPDs exhibit the chameleon-like ability to adopt a weight of 450 Da), BBB permeability decreases by 100-
folded confirmation, reducing their tPSA and achieving fold. 151,152 In addition to size, the compound’s composition,
higher permeability than would be expected based on which determines its physiochemical properties, also
their molecular weight and calculated tPSA. However, regulates BBB permeability. Given that targeted proteins
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the membrane permeation efficiency of TPDs and their are primarily intracellular, aqueous solubility and
attainment of equilibrium across the plasma membrane of cellular permeability are critical for achieving the desired
endothelial cells is expected to be lower than that of typical therapeutic effect. TPDs, by design, can be considered
small molecules. In some cases, however, the reported chemical macromolecules. The high molecular weight
brain concentrations at different time points following IV of TPDs is often associated with low aqueous solubility
injection have been comparable to those observed for small and poor cellular permeability due to a high tendency
molecules. This raises the possibility of BBB disruption- for aggregation or precipitation. This property of TPDs
driven CNS bioavailability rather than permeability- presents significant ADME challenges in the development
mediated bioavailability. Crizotinib and lorlatinib are both of orally bioavailable formulations. Table 5 highlights some
indicated for anaplastic lymphoma kinase-positive non- of the obstacles encountered during the oral delivery of
small cell lung cancer. Their structures, physicochemical TPDs, challenges in estimating plasma protein binding of
properties, and ADME/PK profiles are summarized in TPDs, and major mechanisms of their elimination.
Table 4.
18. Structural modifications of TPDs to
The cyclized version, lorlatinib, has been found to be
effective in reducing the progression of metastatic disease, increase BBB permeability
including brain metastasis. It was assumed to have good Typically, CNS active drugs have ≤3 HBDs, significant
BBB permeability. Consequently, lorlatinib, but not rigidity, fewer rotatable bonds, and a tPSA in the range of
the linear version of crizotinib, has been approved for 60 – 70 Å (with a maximum of 90 Å ). Ideally, for effective
2
2
anaplastic lymphoma kinase-positive metastatic non-small CNS penetration, the number of HBAs and HBDs should
cell lung cancer. be ≤2; however, TPDs often have far more HBAs and HBDs.
However, a single and repeat-dose study of lorlatinib in Despite this, a substantial number of TPDs are advancing
Sprague Dawley rats revealed that lorlatinib administration pre-clinical and clinical development for neurological
increased Evans blue (EB) dye concentration in the brain, indications, for example, XL01126, an Arvinas molecule
indicating damage to the BBB, whereas crizotinib did not (Figure 5).
exhibit this effect. Furthermore, SPP1, VEGF, TGF‐β, and XL01126 has a molecular weight of 1,019.7 Da and
Claudin genes were downregulated in the lorlatinib group, calculated water: octanol partition coefficient of 4.44. The
strongly correlating with the abrupt disruption of BBB. Caco-2 permeability values are A–B <0.74 and B–A <1.43
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Thus, lorlatinib brain exposure is largely attributed to BBB × 10 cm s. Despite possessing unfavorable structural
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/
disruption-driven penetration rather than a permeability- and physiochemical attributes for BBB penetration,
driven mechanism. Another anti-cancer drug, docetaxel, quantifiable concentrations of XL01126 in the CNS have
has also been implicated in destabilizing the BBB, likely been reported in the literature. XL01126 has demonstrated
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driven due to its mechanism of action. In addition to the ability to penetrate the BBB and induce degradation
active ingredients, excipients and inhalant anesthetics of leucine-rich repeat kinase 2. This is particularly
4
can transiently perturb the BBB and increase the CNS intriguing, given the tPSA of XL01126 (194.3 Å ), which
2
bioavailability of drugs. far exceeds the maximum suggested for steady CNS drug
2 153
17. Increasing BBB permeability of entry (90 Å ). The formulation excipients included
10% 2-hydroxypropyl-β-cyclodextrins in 50 mM citrate
chemical macromolecules buffer (pH 3.0) and the dose strength was 1 mg/mL for IV
The brain penetration of compounds primarily depends injection. Male C57BL/6 mice were administered a single
on lipophilicity, affinity for efflux and influx transporters, dose of XL01126 either orally (30 mg/kg), intraperitoneally

Volume 4 Issue 2 (2025) 66 doi: 10.36922/an.5140