Chemical Proteomic Platforms for Radically Expanding Cancer Druggability

Scripps Research Institute, The, La Jolla CA

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Abstract

PROJECT SUMMARY Advances in genome sequencing and editing have greatly accelerated the discovery of genes and proteins that make fundamental contributions to tumorigenesis. Some of these proteins have been targeted by groundbreaking medicines. Many cancer-relevant proteins, however, lack chemical probes and are even considered undruggable. In these cases, our understanding of the molecular basis of cancer has not yet translated into new therapies. The goal of this Outstanding Investigator Award (OIA) renewal application is to leverage and extend our lab’s innovative activity-based protein profiling (ABPP) technologies to radically expand the druggable content of the human proteome and develop first-in-class chemical probes for a diverse array of cancer-relevant proteins. In the previous funding period, we made several fundamental innovations and advances, including: 1) the introduction of stereochemically defined libraries of electrophilic compounds (‘stereoprobes’) that accelerate the discovery of cryptic ligandable pockets on cancer-relevant proteins; 2) the identification and functional characterization of first-in-class covalent ligands for numerous strongly selective cancer dependency proteins, including historically undruggable transcription factors, RNA-binding proteins, and adaptors; 3) the discovery of mono- and heterobi-functional ligands that promote the degradation of cancer-relevant proteins through covalent targeting of E3 ligases and their substrates; and 4) the introduction of ABPP methods such as paralog hopping for expanding the ligandability of cancer proteomes beyond covalent chemistry. These achievements have also had a broad impact on cancer therapeutics, where our ABPP platforms have served as a foundation for the development of several novel drug candidates targeting selective cancer dependency proteins that are under clinical investigation. In our future research program, we, along with our extensive set of biology and chemistry collaborators, will continue to lead the field of chemical proteomics-guided cancer ligand and drug discovery by pursuing innovations that include: 1) novel stereoprobe library designs to further expand the ligandability of cancer proteomes, including covalent chemistries that extend beyond cysteine; ii) the development of diverse “function-first” assays for prioritizing covalent ligands that target cryptic pockets on cancer-relevant proteins; 3) the leveraging of liganding events on DNA/RNA- binding proteins to create programmable approaches for suppressing pro-tumorigenic transcriptional processes in cancer cells; and 4) the advancement of ABPP methods to discover ligands that specifically target cancer-relevant proteoforms of proteins. In summary, with this OIA, we will build on our track-record of innovation and achievement to realize the ultimate goal of bringing each and every cancer-relevant protein into the realm of druggability for the benefit of basic and translational research.