University of Dundee

EASTBIO iCASE: Novel bifunctional chemistries for unbiased exploration of targeted protein degradation mechanisms

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.

This is an iCASE studentship supported by Tocris, a leading innovator in life science reagents and research tools and would include a minimum 3-month placement at their state-of-the-art UK laboratories.

Dr. Farnaby has made major contributions towards the understanding and generation of targeted protein degrader chemical probes against cancer targets previously considered undruggable, such as ACBI1 and ACBI2 for the BAF chromatin remodeling complex subunits SMARCA2/4 [2;3]. Previous to his ground-breaking discoveries in the application of PROTACs for cancer, he spent several years as a senior medicinal chemist in industry, co-inventing two central nervous system drugs currently in late-stage clinical trials. The vision for his group combines expertise in central nervous system research and chemical biology / medicinal chemistry.

The Ciulli Lab is one of the pioneering laboratories in the fields of PROTACs. The lab has revealed fundamental insights into the working of PROTAC degrader molecules that they have designed and that are used across the globe [4].

References:

  1. Farnaby, Koegl et al, Curr Opin Pharmacol, 2021;57:175-183
  2. Farnaby et al, Nat Chem Biol 15, 672-680 (2019)
  3. Kofink  et al, ChemRxiv DOI: 10.26434/chemrxiv-2022-q63s3
  4. Ishida & Ciulli, 2021 Apr;26(4):484-502

Please note the closing date for this project is Friday 29th April 2022

Eligibility