UC Berkeley

While many disease-modifying protein targets have been discovered, most of these targets have remained untranslated as they are considered to be difficult to target with small-molecule drugs. In fact, most of the proteome is devoid of pharmacological tools, greatly hindering both basic and translational research efforts. Studies have demonstrated that the development of high-quality chemical tools for proteins of interest catalyze research into the function and therapeutic exploitation of those proteins, thus correlating the development of chemical tools for specific proteins with their associated research activity.1 In fact, only 2% of all predicted human gene products are currently targeted with small-molecule drugs and only 10-15% of all human genes are thought to be ‘druggable,’ with only a 25% overlap between druggable protein targets and known disease-modifying targets.2 Therefore, it is crucial to develop novel approaches and pharmacological tools that garter the entire proteome if we hope to accelerate drug discovery efforts towards curing complex diseases.

The use of reactivity-based chemoproteomic probes and isoTOP-ABPP platforms has afforded the discovery of numerous sites within proteins that may represent a variety of functions such catalytic activity, protein- protein interactions, and allosteric regulation.3–6 In this dissertation, I present evidence of how chemical genetics and chemoproteomics approaches can be coupled to not only identify novel anti-cancer protein targets, but also covalent small molecule compounds that can inhibit or impair said targets. I also demonstrate how chemoproteomics as a whole allows for the target identification of almost any small molecule of interest, therefore accelerating drug discovery platforms by identify lead targets and the general promiscuity of a lead ligand. Overall, I provide work that details how we have identified novel sites within protein targets that can be drugged, as well as novel protein targets themselves. This work demonstrates how chemoproteomic platforms, when applied to multiple drug discovery platforms, allows for the rapid identification of novel anti-cancer covalent compounds, and their targets, ultimately providing an approach that can have a large impact on the fight to cure cancer.