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Technology-driven drug discovery
Chemoproteomics
Chemical proteome profiling. Proteins are the primary functional mediators of cellular phenotypes in biological systems. Under drug perturbation, the proteome can undergo moderate to profound changes in abundance, modification state, localization, and complex formation. Systematic assessment of these drug-induced proteome and post-translation modification (PTM) changes is therefore essential for elucidating mechanism of action (MOA), understanding off-target effects, and guiding rational drug design and combination therapies.
Activity-based proteome profiling (ABPP). Among nucleophilic residues, cysteine, lysine, serine, histidine, and arginine have been systematically studied, and diverse electrophilic “warheads” have been developed to target these residues selectively or non-selectively. Some of them such as cysteine and lysine are central to catalysis, regulation, and signaling because of their high chemical reactivity. However, their functional roles are often difficult to predict from sequence or structure alone, as they typically lack clear consensus motifs. Chemoproteomic approaches based on ABPP have therefore emerged as powerful strategies to globally map the reactivity, ligandability, and functional relevance of these residues directly in complex biological systems. We dedicate to develop scalable, high-throughput ABPP technologies support target identification and mechanism-of-action studies. These integrated MS-based approaches provide a coherent framework for linking chemical perturbations to functional proteome remodeling, expanding the druggable proteome, and accelerating therapeutic development.
Proximity-induced protein modification and covalent drug discovery
Proximity-induced protein modification (PIPM). Degraders such as PROTACs promote ubiquitination and subsequent proteasomal degradation of target proteins, commonly referred to as the protein of interest (POI). Proteomic technologies have been central to this field, enabling proteome-wide assessment of degradation, target selectivity, and ubiquitination dynamics. The essential mechanism of is to use chemically induced proximity to remodel protein fate. This concept has now been extended beyond the ubiquitin-proteasome system to other PTMs, by utilizing functional enzymes such as kinases and deubiquitinases. Proteomics will remain crucial for monitoring these induced modifications, and continued development of chemoproteomic methods will be needed to keep pace with these alternative approaches.
Covalent drug discovery. Covalent drugs carry a mildly reactive group that forms a bond with a target residue, adding affinity and often prolonging target engagement. Over the past ~30 years, rational design has shifted toward targeting non-conserved residues to improve selectivity, yielding successful drugs against previously considered “hard-to-drug” targets. Two main discovery routes now dominate: structure-guided incorporation of electrophiles into otherwise reversible ligands, and “electrophile-first” screening of electrophilic libraries. Because nucleophilic residues can be systematically probed by electrophiles, multiple MS-based chemoproteomic methods have been established to profile residue reactivity and ligandability, enabling discovery of selective covalent ligands for previously “undruggable” proteins.
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