Recent chemoproteomics advances have enabled covalent ligand discovery across a broad range of new targets.  Here, we discuss the expanding role of chemical biology and chemoproteomics to support covalent lead discovery efforts, from early hit-finding to late lead optimization.

In this talk, I will discuss some of the medicinal chemistry done to optimize a covalent small molecule inhibitor of the anti-apoptotic protein BFL1. I will then discuss how targeted proteomics were used to monitor the impact of compound treatment on target half-life and to determine target occupancy.

This presentation will describe our utilization of clickable chemical biology probes to assess target engagement and conduct selectivity profiling to identify off-targets in two drug discovery endeavors featuring covalent inhibitors. In both instances, thorough selectivity profiling across multiple cell types was pivotal, allowing for a more comprehensive identification of potential off-targets that could pose safety concerns.

Small molecules that chemically induce proximity are powerful approaches to rewire the circuitry of the cell. My talk will describe our recent advances in the development of chemical-genetic tag-based platforms to precisely modulate protein levels, stability, and activity. I will also describe our work to apply these approaches for biological investigation and pre-clinical target discovery and validation.

Molecular glues engaging protein complexes have reshaped cell biology and clinical oncology. Despite this, discovering new glue classes has been largely serendipitous. We introduce molecular COUPLrs, featuring dual cysteine-reactive warheads, alongside CONNECT, a chemical proteomics platform for target analysis. By profiling COUPLrs in 13 cancer cell lines, we identified numerous proteins for coupling, and developed an advanced COUPLr targeting EML4-ALK, disrupting its signaling and dynamics.

A major class of tumor immunotherapeutics function by bridging immune machinery with tumor antigens, highly expressed on cancer cells compared to normal tissue. Antibody-recruiting molecules represent an emerging synthetic immunotherapeutic strategy to bridge serum antibodies with these tumor antigens, leading to Fc receptor-mediated anti-tumor function. In this seminar, we describe the development of a new chemical strategy that uses covalent chimeric molecules, to enhance antibody recruitment to cancer cells and induce tumor cell-immune cell proximity. The covalent engagement of serum antibodies affects unique anti-tumor functional enhancements, generating new hypotheses surrounding immune receptor pharmacology.

The integration of covalent chemistry with chemoproteomics has catalyzed the identification of novel small molecule binding pockets across the proteome. This talk will describe key features of the HYKU platform including warhead development for covalent screening of histidine, tyrosine, and lysine (HYK) residues; optimizing mass spectrometry-based chemoproteomics for non-cysteine amino acids; and integration of structural information to prioritize novel binding pockets for further development of covalent or non-covalent compounds.

TATA-box binding protein associated factor 1 (TAF1) is involved in transcriptional regulation of cancer development and progression. However, current TAF1 inhibitors have limited efficacy. Using ZS3-025, a CRBN-based PROTAC for TAF1, we show that degradation of TAF1 exhibited broad sensitivity across various cancerous and non-cancerous cell lines, highlighting the necessity for a more precise approach to targeting TAF1.