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.

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…Degradation approaches have been examined in proof-of-concept studies for neurodegenerative diseases ( Thomas et al, 2023 ). Conceptually, protein or aggregates can be degraded if a selective small molecule binder is available.…”

Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders

“…The accumulation of mutated tau species into neurofibrillary tangles, both in the intracellular and extracellular space, leads to cellular toxicity and neuronal cell death [195]. Different peptide-based and small-molecule-based PROTACs have been developed for tau degradation.…”

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

“…Additional novel DYRK1A inhibitors have been identified that can induce DYRK1A degradation that can be useful for decreasing the dosage of the expressed protein in AD and DS , but further research is required to evaluate their potential for therapeutic use ( Branca et al, 2017 ; Melchior et al, 2019 ; Velazquez et al, 2019 ). Finally, normalization of the DYRK1A function in AD and DS could be achieved by developing the approaches for decreasing the protein levels without targeting its catalytic activity, such as use of PROteolysis Targeting Chimeras (PROTACs) ( Choudhary et al, 2023 ; Thomas et al, 2023 ).…”