Sofia Hu

• CDT Doctoral Researcher (Aligned) Supervisor: Dr Hannah Stewart
• Email: S.Hu17@newcastle.ac.uk
• Project title: Hydrophobic warheads to expand covalent drug discovery

Institution: Newcastle University

Project summary: Targeted covalent inhibitors (TCIs) offer opportunities to drug previously undruggable targets by forming permanent covalent bonds with proteins. Most TCIs use acrylamide warheads, whose polarity can limit their compatibility with hydrophobic protein pockets.

Previous research has shown that alkynes attached to electron-deficient heterocycles can act as covalent warheads. Their increased hydrophobicity may enable targeting of cysteine residues in more hydrophobic environments, expanding the scope of covalent drug discovery. However, these warheads have yet to be applied to covalent mapping and screening.

This project will design and synthesise a library of alkynyl-warhead compounds incorporating a terminal carbon-13 label. NMR spectroscopy will identify covalent fragment hits through carbon-13 chemical shift changes, with protein-observed 2D NMR and X-ray crystallography used to validate hits and establish modification sites, aided by anomalous scattering from halogen atoms. The resulting library and screening methods will be used to map and identify new drug discovery starting points for high-value oncology targets.