Medulloblastoma (MB) is one of the most prevalent malignant brain tumours in children, representing around 20% of all paediatric brain tumours1. Despite therapeutic advances, around 30% of patients succumb to the disease, and surviving patients go on to endure long-term side effects from treatment, which markedly impair quality of life2. Hence, there is a need for novel, more selective therapeutic strategies for MB. Current drug development approaches are limited by their focus on ‘well-characterised’ active protein sites, overlooking a large proportion of the proteome considered “undruggable”.
This project aims to map the ligandable proteome of MB using activity-based chemical probes to prioritise and validate biologically relevant targets and promising chemical probes for target-based drug discovery. An in-house compound library containing commercially available and proprietary cysteine-directed covalent fragments, will be used to screen ligandable targets in medulloblastoma cells. Candidates will then be validated by using chemical biology, chemoproteomics and functional genomics tools. The most promising targets will then be evaluated in preclinical in-vivo models to assess therapeutic efficacy and translational potential.
Preliminary screening of our library has revealed potential candidate chemical probes that fulfill selection criteria: (i) drug-like chemical features such as synthetic accessibility and predicted blood brain barrier permeability (ii) selective cytotoxic activity to MB cells relative to the non-cancerous MRC5 cells (<5-10fold). These chemical probes will subsequently be used to map the ligandable proteome of medulloblastoma cells.
Ongoing target validation and biological relevance of mapped targets, in cancerous relative to non-cancerous cells, will determine the potential of prioritised target/ligand pairs for preclinical studies. This approach offers a promising path towards developing more selective and less toxic treatments for paediatric medulloblastoma.