Chemoproteomics-Enabled Covalent Ligand Discovery Platforms for Accessing Novel Druggable Modalities

ASPIRE Award

Dr. Daniel Nomura from the University of California, Berkeley is working with his team to make drugs for cancer targets that have traditionally been considered “undruggable”. In general, small molecule drugs target proteins by binding to a pocket or cleft in the protein and changing its function. More than 90% of human proteins, however, do not have an obvious binding pocket. Dr. Nomura and team are using activity-based protein profiling to map hotspots on proteins that can bind to or react with a small molecule. The team has already discovered more than 100,000 such hotspots in more than 20,000 human protein targets – revealing binding sites across almost all human proteins that can form the basis for developing new drugs. Many of these binding sites are on proteins that are known to drive cancer. Dr. Nomura is developing ligands against previously undruggable cancer protein targets by screening libraries of drug-like compounds against the newly discovered hotspots and determining if these compounds are likely to function in vivo.
As part of this ASPIRE Award, one of the targets Dr. Nomura is focusing on is the transcription factor brachyury, a protein that has been shown to drive the development of chordoma, a rare bone cancer of the spine and skull. The brachyury-targeting aspect of this project was also awarded a Therapeutic Innovation Award jointly with the Chordoma Foundation.