ACTIVITY-BASED PROTEIN PROFILING - CANCER TARGET AND DRUG DISCOVERY ON A GLOBAL SCALE

Advances in genome sequencing and genome editing technologies have greatly increased our understanding of the molecular basis of cancer and nominated many new cancer targets. However, many of cancer-relevant proteins lack small-molecule probes and even considered historically undruggable. To address these problems, we have introduced activity-based protein profiling (ABPP), a chemical proteomic technology that globally profiles the functional state and small molecule interactions of proteins in native biological systems. In this lecture, I will describe the application of ABPP to generate covalent small molecule interaction (or ligandability) maps of human cancer cells and how this information can guide the discovery of first-in-class chemical probes and drug candidates for cancer-relevant proteins. Key themes will include: 1) the importance of assaying proteins in endogenous environments to realize their full small molecule interaction potential; 2) the capacity of covalent chemistry coupled with ABPP to extend the druggability of the proteome to reach historically challenging target families like adaptor/scaffolding proteins and DNA/RNA-binding proteins; and 3) the remarkably diverse ways that allosteric small molecules can regulate protein function in cells.