Outcome of the Carnegie/Caledonian PhD Scholarships Round…
Project Title: Development of Latent Esters as Novel Ligands for Intrinsically Disordered Protein Domains
In the UK, one in eight men will be diagnosed with prostate cancer at some point in their lives. The androgen receptor (AR) is responsible for growth and maintenance of both normal and cancerous prostate tissue. Studies have shown the N-terminal domain (NTD) of the AR is essential for receptor function, making it a promising drug target; however, the disordered nature of this domain makes drug development challenging as common strategies like structure-based drug design cannot be used.
Reactive fragments are an emerging method of hit identification however current approaches suffer from off-target effects and low efficiency. This project aims to avoid these issues by employing a latent active ester (LAE) approach for fragment screening. Tetrazoles can be activated by light to form reactive nitrile imine intermediates which rearrange to LAEs. A fragment library of compounds containing the tetrazole warhead will be synthesised and screened against the AR NTD, with which they will form amide bonds. Biophysical techniques will be used to identify hit compounds which will then be synthesised without the tetrazole warhead and further validated in a biological assay. Results from this assay can be used to inform decision making in further optimisation efforts to identify potent compounds.
Awarded: Carnegie PhD Scholarship
University: University of Strathclyde