Chemical proteomic discovery of covalent ligands for novel drug targets in Myc-deregulated cancers

Myc oncogenes (such as c-MYC) are deregulated in >70% of all cancers, where they promote transcriptional activation of genes involved in protein synthesis and cancer metabolism. c-MYC is among the most important oncogenes (drivers of cancer) and one of the most sought-after cancer drug targets. However, c-MYC exemplifies the features of an "intractable" drug target, being largely disordered and lacking clearly identifiable ligand binding sites, and despite decades of research it has yet to yield to small molecule drug discovery.

In this project, we will develop a new approach to targeting Myc-deregulated cancers by discovering changes in the reactivity and covalent ligandability of cysteine residues caused by c-MYC actively driving tumorigenesis. Using chemical proteomics, which exploits chemical probes for cysteine ligandability coupled to enrichment and high-throughput mass spectrometry proteomics, we can discover and quantify c-MYC-dependent changes across the entire proteome, including but not limited to c-MYC itself. These alterations represent potential novel drug targets for Myc-deregulated cancers and may be driven by differences in post-translational modification (e.g. modifications at cysteine such as oxidation or acylation), protein interactions (e.g. shielding or exposure of cysteines due to gain or loss of a binding partner or protein-DNA interaction), or changes in protein expression. In parallel we will also examine the scope for degradation and stabilisation of targets through covalent modification, encompassing the rapidly emerging field of covalent molecular glues.

You will develop chemical proteomic technologies at the cutting edge of chemical biology, using synthetic chemical probes bearing a cysteine-reactive group (or "warhead") and recent advances in high-throughput proteomics, to enable both identification of altered cysteine reactivity and high-throughput proteomic screening against a carefully designed library of diverse covalent ligands. You will apply this platform to cancer cells as they transition from low to high c-MYC states, to identify critical novel vulnerabilities in the Myc-deregulated cancer proteome; these rich datasets will provide the basis for understanding the biology of Myc-deregulated cancers, and potential starting points for covalent drug discovery.