Targeted protein degradation (TPD) technologies, exemplified by PROTAC and molecular glue, represent a revolutionary drug discovery paradigm that operate through an "event-driven" mechanism. These technologies are widely utilized in chemical biology research and drug discovery, successfully advancing over 50 innovative drugs into Phase 1–3 clinical trials. However, current generation of targeted protein degraders face several significant limitations: (1) still difficult to challenge “unligandable” targets such as transcription factors; (2) the E3 ligase toolbox are largely limited to CRBN and VHL; (3) the therapeutical indications are largely limited to cancer; (4) Targeted extracellular protein degradation by small molecules has not been realized. These critical bottlenecks collectively hinder the further development of TPD field.

Our research interest focuses on the development of small molecule drug discovery based on TPD technologies and target validation with the developed small-molecule degraders. Our group aims to overcome current critical bottlenecks in the TPD field and develop the next-generation of targeted protein degraders to largely expand the target and indication scope. In addition, our group are also interested in the development of novel small-molecule therapeutics by exploring new chemically-induced proximity modalities. Specific research directions include:

(1) Rational discovery of highly selective molecular glue degraders for transcription factors;

(2) Discovery of small molecule ligands for underexplored E3 ligases to expand the E3 ligase toolbox beyond CRBN/VHL;

(3) Development of targeted protein degraders for the treatment of inflammatory and neurodegenerative diseases;

(4) Targeted extracellular protein degradation via heterobifunctional small molecules;

(5) Development of novel bifunctional anticancer inhibitors utilizing new chemically-induced proximity modalities.