Central Nervous System Targeted Protein Degraders

Abstract

Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines—primarily due to the well cited challenges in target validation, valid translational models, and clinical trial design. Unfortunately, this decline in research and development interest has occurred in tandem with an increase in the medical need—in part driven by the success in treating other chronic diseases, which then results in a greater overall longevity along with a higher prevalence of diseases associated with ageing. The lead modality for drug agents targeting the brain remains the traditionally small molecule, despite potential in gene-based therapies and antibodies, particularly in the hugely anticipated anti-amyloid field, clearly driven by the additional challenge of effective distribution to the relevant brain compartments. However, in recognition of the growing disease burden, advanced therapies are being developed in tandem with improved delivery options. Hence, methodologies which were initially restricted to systemic indications are now being actively explored for a range of CNS diseases—an important class of which include the protein degradation technologies.