Blood Brain Permeability And CNS Bioavailability Of Targeted Protein Degraders

By Satinder Singh, Satish Kumar, Sudhir Tiwari, Surendra Yadav Ravulapalli, Srinivas Lenkalapelly, Narayanasamy Duraisamy, and Pratima Srivastava DMPK- Biology, Aragen Life Sciences Limited., Hyderabad, India.

Within the field of central nervous system (CNS) disorders, there is a critical demand for innovative therapies that can directly address underlying proteinopathies. One emerging class of modalities with significant potential is Targeted Protein Degraders (TPDs). While their relatively large molecular size and physicochemical complexity have raised questions about their ability to cross the blood–brain barrier (BBB), early studies have demonstrated that certain TPDs can indeed achieve measurable concentrations in the brain and cerebrospinal fluid. This encouraging evidence suggests that, with careful molecular design, the inherent flexibility of TPDs can be leveraged to optimize key parameters such as solubility, permeability, and oral bioavailability, while still maintaining BBB penetration.

A central focus of this discussion is the interplay between the absorption, distribution, metabolism, and excretion (ADME) properties of TPDs and their CNS pharmacokinetics. Particular attention is given to how these compounds interact with drug transporters at the BBB—both efflux and uptake pathways—which can dramatically influence brain exposure. By correlating physicochemical attributes with in vivo pharmacokinetic data, new insights are beginning to emerge on how to fine-tune TPD design for CNS applications.

Exploring these dimensions not only broadens the therapeutic potential of TPDs in neurodegenerative and psychiatric diseases but also provides a framework for overcoming one of the most persistent challenges in CNS drug discovery: effective delivery across the BBB. Unlocking this relationship between molecular properties, transporter interactions, and brain distribution may pave the way for a new generation of protein degradation strategies specifically tailored to treat CNS disorders.