Research
The overarching goal of our research program is to expand the druggable proteome by developing innovative small molecules. While small molecules account for over 70% of FDA-approved drugs, less than 10% of the ~20,000 proteins encoded in the human genome are currently targeted by small molecules. Many of these untargeted proteins are thought to be “undruggable” and belong to the “dark proteome” due to the absence of suitable binding pockets for small molecule interactions.
To address this challenge, our research focuses on leveraging induced proximity-based pharmacology to develop chemical probes for undruggable proteins. Heterobifunctional molecules, such as proteolysis targeting chimeras (PROTACs), have demonstrated success in this area by inducing targeted protein degradation. However, these approaches are often constrained by the need for ligandable sites and the suboptimal pharmacokinetic properties associated with their relatively high molecular weights.
One promising solution 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. As a result, there is a pressing need for a more systematic and scalable approach to discovering molecular glues, particularly those that target undruggable proteins.
Our lab aims to address this gap by integrating chemical biology, protein biochemistry, medicinal chemistry, functional genomics and proteomics to enable the rational discovery of molecular glues. 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:
- Targeted protein degradation: Shifting the paradigm from target inhibition to target degradation, enabling the therapeutic targeting of “undruggable” cancer proteins
- Induced proximity beyond degradation: Pioneering novel therapeutic modalities that leverage induced proximity beyond protein degradation
- Chemical biology for T cell modulation: Harnessing small molecules to reprogram immune cell fate and enhance immunotherapy response
- Tackling challenging cancer targets: Developing selective small molecule chemical probes to address challenging oncogenic drivers