Hojong Yoon

The Yoon Lab focuses on developing innovative small-molecule drugs to target previously undruggable proteins and to elucidate drug mechanisms at the molecular level. By integrating chemical biology, protein biochemistry, medicinal chemistry, functional genomics and proteomics, the lab aims to develop new small molecules that induce novel protein-protein interactions, opening new avenues for therapeutic intervention and redefining 'druggability' Our particular interest is the 'molecular glue' approach, which employs a monovalent small molecule that stabilizes the interface between two proteins that do not normally interact. This induced protein-protein interaction not only enables neomorphic pharmacological effects, but can be applied to proteins with shallow or absent binding pockets, greatly expanding the repertoire of druggable proteins. Examples of molecular glues include the immunosuppressant cyclosporine A, as well as lenalidomide, an FDA-approved drug for the treatment of multiple myeloma. Lenalidomide recruits neosubstrates IKZF1 and IKZF3, which were previously considered undruggable due to the lack of ligandable sites, to the E3 ligase CRBN, resulting in their polyubiquitination and proteasomal degradation. While their efficacy and utility have been widely validated, the discovery of most molecular glues has been serendipitous, and as of now, there is no established method for systematically identifying them at scale. By establishing systematic approaches for identifying and characterizing these compounds, we seek to expand the druggable proteome and develop novel therapeutic strategies. In addition, we aim to use these molecular glue-based chemical probes to uncover new biological insights, further advancing our understanding of protein function and interaction networks. Through these efforts, we strive to redefine druggability and drive innovation in proximity-driven pharmacology and therapeutics. Our lab focuses on these key areas: 1. Targeted protein degradation 2. Induced proximity beyond degradation 3. Chemical biology for T cell modulation 4. Tackling challenging cancer targets