Within the Cancer Research UK Newcastle Drug Discovery Programme, we run a portfolio projects focused on identifying new molecules for novel cancer targets in areas of unmet medical need. We focus particularly on treatments for drug resistant cancers and to high value challenging targets such as protein-protein interactions. These projects involve cutting-edge structure based drug design and employ modern methods for hit generation and optimisation. In particular, we focus on fragment-based lead generation, DNA-encoded libraries and covalent inhibition.