Many proteins exist in unique conformations or form interactions present only within their native cellular environment. We have developed proteome-wide cysteine profiling methods and identified covalent fragments with high occupancy for therapeutically relevant targets. Key insights, examples, and lessons learned will be presented.

Inherent proximity of cell surface protein environments not only influences how proteins function but also informs our ability to effectively target/modulate cell surfaces for therapeutic benefit. This talk will describe the development of a novel light-mediated catalytic proximity labeling toolbox for identifying proximal protein environments for clinically-relevant surface proteins as well as downstream applications of the technology.

Targeted covalent inhibitor (TCI) approaches are an emerging small molecule drug modality where a covalent bond between a drug and a target protein forms by design. TCI drugs are regaining momentum as an attractive small molecule drug modality that can be applied to protein targets which have been previously considered undruggable. This presentation will discuss the challenges and strategies for the development of TCI drugs from absorption, distribution, metabolism, and excretion (ADME) perspective. Unique assays are required to support development of TCIs and will be presented with examples.

With Stuart Schreiber’s group we developed chemical inducers of proximity to probe the role of this fundamental physical process in biologic mechanisms such as signal transduction, transcription, epigenetics as well as protein location, regulation and stability.  These early studies used genetically tagged proteins or nonspecific small molecules, but pointed the way to approaches using no genetic tags that capitalize on underlying biologic specificity. I will discuss some of the later in more detail.