The central challenge in modern drug discovery is that the vast majority of disease-driving proteins remain undruggable by conventional small molecules. Our laboratory develops chemoproteomic technologies to systematically uncover cryptic ligandable hotspots throughout the human proteome and transform these previously inaccessible proteins into tractable therapeutic targets. Using quantitative chemoproteomics, we have mapped more than 100,000 ligandable sites across over 16,000 human proteins, including ligandable hotspots within the majority of genetically linked cancer drivers. These maps provide a foundation for discovering covalent ligands against transcription factors, intrinsically disordered proteins, signaling proteins, and other historically undruggable targets. We integrate large-scale covalent ligand screening with chemoproteomic target deconvolution to rapidly identify functional covalent ligands, define their proteome-wide selectivity, elucidate mechanisms of action, and optimize therapeutic leads. By combining synthetic chemistry, chemical biology, proteomics, and disease biology, our goal is to establish a generalizable platform for developing first-in-class therapeutics against the undruggable proteome.

Targeted protein degradation (TPD) has transformed the way we think about drug discovery by enabling the selective elimination of disease-causing proteins rather than simply inhibiting their activity. Our laboratory develops next-generation TPD technologies that dramatically expand both the range of degradable proteins and the cellular machinery that can be harnessed for degradation. A major limitation of current degradation strategies is the scarcity of ligands for both undruggable targets and E3 ubiquitin ligases. We address both challenges through chemoproteomic discovery platforms that identify covalent ligands against disease-associated proteins as well as novel recruiters of E3 ligases and other components of the cellular protein quality control machinery. These discoveries enable the creation of innovative degrader architectures that extend beyond conventional PROTACs. In parallel, we are developing systematic approaches for discovering and engineering molecular glue degraders. Rather than relying on serendipitous discoveries, we combine chemoproteomics with phenotypic screening and proteome-wide target deconvolution to identify small molecules that induce productive protein-protein interactions and rapidly define the molecular basis of their activity. Together, these efforts establish new principles for programmable protein degradation across the proteome.

Induced proximity represents a fundamentally new paradigm for drug discovery. Rather than simply inhibiting or degrading proteins, induced proximity therapeutics create entirely new protein interactions that reprogram cellular function through gain-of-function mechanisms. Our laboratory is pioneering new classes of induced proximity therapeutics that extend far beyond targeted protein degradation. By combining chemoproteomics with heterobifunctional molecules and molecular glues, we develop technologies that recruit diverse cellular proteins and enzymes to rewire biology in programmable ways. These platforms enable transcriptional repression and activation, protein stabilization, signal rewiring, epigenetic reprogramming, and other emerging therapeutic modalities. A major focus of our research is the development of programmable transcriptional therapeutics that selectively reprogram gene expression through targeted recruitment of chromatin regulators and transcriptional machinery. More broadly, we seek to establish a comprehensive toolkit of induced proximity strategies capable of controlling virtually any protein function, ultimately creating entirely new therapeutic modalities for diseases that remain beyond the reach of conventional pharmacology.