Novel bifunctional chemistries for unbiased exploration of targeted protein degradation mechanisms

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Small molecules that can selectively target proteins for degradation, as appose to simply inhibiting their function, are proving to be invaluable research tools for life scientists to understand a wide range of cellular function and provide the potential for a new generation of breakthrough therapeutics. Proteolysis Targeting Chimeras (PROTACs) are two-headed molecules that achieve this goal by simultaneously binding with one head to a target protein and with another head to an E3 ubiquitin ligase, thus inducing the proximity and ubiquitination/degradation of the target protein. Such approaches to date have been largely utilised in the context of understanding and treating cancer [1]. Application of these or similar tools to understand a broader array of biological contexts is limited by a narrow understanding of mechanisms via which the ubiquitin proteasome system (UPS) can be re-directed to degrade a chosen target protein. This limitation is particularly acute in the central nervous system where there are specific protein expression signatures and additional challenges for small molecule tissue accessibility that limit applicability of classical targeted protein degradation approaches.This project will focus on developing innovative chemical library synthesis and testing approaches to deliver tools that selectively degrade protein(s) implicated in a wide range of neuronal function, in a mechanism unbiased fashion. This will enable exploration of novel concepts that have potential to transform our understanding of how the UPS can be harnessed and purposefully directed within the central nervous system. To achieve this goal methods and reagents will be developed that will find utility amongst the many life science research groups and organisations currently pursuing proximity inducing modalities, including but not limited to targeted protein degradation.