The central questions that motivate our work relate to understanding the epigenetic drivers of genome structure and function in cancer. Our studies are revealing fundamental targeting roles for oncogenic transcription factors, with new insights into the altered epigenetics. Our training environment is highly interdisciplinary, with projects including the development of rigorous normalization methodology to determine “global” differences in chromatin states. We incorporate kinetic studies, including induced protein degradation, to examine immediate/early functions of epigenetic processes. 

While the past 20 years have seen impressive progress in developing inhibitors of protein-protein interactions (PPIs), PPI stabilization is a relatively untapped approach for manipulating protein interaction networks involved in homeostasis and disease. We have utilized a fragment-discovery approach called disulfide tethering to systematically discover stabilizers for the PPI hub protein 14-3-3, which binds to hundreds of phosphorylated proteins.

Emerging targeted therapeutic modalities leverage the ability of our own immune system, to recognize and eliminate diseased cells and foreign pathogens. Chemical biology can contribute tools with the unique ability to enhance the proximity of key immune receptors with these disease targets to enforce a therapeutic response. To explore the molecular requirements and physical properties governing immune function, we have developed new classes of proximity-inducing molecules that use covalent chemistry to enforce immune receptor binding interactions. This talk discusses current progress in the use of covalent immune recruiting molecules to modulate antibody-dependent eradication of cancer and mechanistic insights into key factors governing anti-tumor potency and efficacy. 

Chemical modifications on RNAs play pivotal roles in RNA regulation and have been linked to different human diseases. However, research tools to dissect their biological functions are still very limited. In this talk, I will discuss our efforts in developing spatiotemporal-specific tools that integrate chemically induced proximity and CRISPR technologies to edit specific RNA modifications on chosen RNA transcripts in cells.

Here I will give an overview of Amgen's Induced Proximity Platform with a focus on our Targeted RNA Degradation effort. I will review new approaches to characterize novel RNases for development of RIBOTACs. Finally, I'll highlight our progress in the discovery of new chemical ligands for RNases previously not developed for Targeted RNA Degradation.