Research
Small Molecule Induced Proximity
Nearly every biological process in the cell depends on interactions between proteins, which when altered through mutations or external factors, can lead to aberrant cell function, and result in disease such as cancer. Small molecule protein inhibition through ‘loss of function’, is the centerpiece of therapeutic intervention and the therapeutic potential of the ‘gain of function’ associations through ligand induced proximity have only begun to be explored with transformative studies on E3 ubiquitin ligases. What are the functional consequences of small molecule induced proximity? How to utilize these for patient benefit? We aim to address this by developing tools to harness the power of the neo-interactome to study biology, rewire the cell and explore its therapeutic application in cancer and immunology.
Targeted Protein Degradation
Small-molecules that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. Over the past years two major approaches emerged: molecular glues degraders, exemplified by immunomodulatory drugs (IMiDs) thalidomide and lenalidomide which bind their cognate E3 ligase adapter CRBN and possess no measurable affinity to the neo-substrate, and proteolysis targeting chimeras (PROTACs), where an E3 ligase binder is tethered to a target binder, both resulting in induced proximity and as a consequence protein degradation. These approaches have distinct characteristics: serendipitous in nature, but more drug-like molecular glue degraders, and less drug-like, but enabled through modular design PROTAC molecules. We study how these modalities work on the molecular level, leverage existing knowledge to more efficiently design them and develop tools to find new molecular degraders at scale.
Molecular glue degrader ALV1. ALV1 recruits IKZF2 transcription factor to CRL4CRBN and results in its degradation. Adapted from Wang et al., NCB 2023.
Technology Development
Small molecule inducers of proximity resulting in degradation (when an E3 ubiquitin ligase is recruited), or by posttranslational modulation (by recruiting other effector proteins such as kinases, phosphatases, epigenetic modifiers) or alter protein localization, while being therapeutically exciting, also form excellent set of chemical biology tools to study protein function. Protein fusion tags that enable targeted protein degradation (such as dTAG) have been valuable tools to dissect rapid biology with full small molecule control. We aim to leverage these and develop new tools to study induced proximity at scale.
