Zhongrui Zhang, Pharmaceutical Sciences graduate student (Tang Research Group), will be defending his PhD research thesis:

Expanding the Horizon of Proteolysis Targeting Chimeras (PROTACs): RAPID Platforms, CLIPTAC, and the Exploration of E3 Ligase Substrate Receptors

In this dissertation, innovative strategies were developed to advance Proteolysis Targeting Chimeras (PROTACs) for therapeutic applications. Chapter 1 presents the design of RAPID-TAC and RAPID-GLUE, two novel platforms that expedite the discovery and optimization of PROTACs. Included in this chapter is the successful application of these strategies towards the development of degraders for Receptor Interacting Protein Kinase 1 (RIPK1), which shows promise in advancing cancer immunotherapy. Further, this chapter unveils the second generation of the RAPID-TAC platform, revealing its efficiency in producing a wider array of BRD4 degraders. Finally, a cutting-edge platform, RAPID-GLUE, is introduced for the swift synthesis of molecular glues for direct biological screening. In Chapter 2, a breakthrough in PROTACs assembly is achieved by developing an in-cell self-assembly method that employs covalent E3 ligase ligands. This chapter brings to the fore an innovative tactic that bypasses the need for individual PROTAC synthesis, thus expediting the degradation of target proteins. Chapter 3 probes the potential of DDB1 and CUL4-associated factors 1 (DCAF1) and 15 (DCAF15) as new E3 ligase substrate receptors for PROTACs. Through rigorous experimentation, it is demonstrated that DCAF1 and DCAF15 are effective in mediating the degradation of BRD4 and Androgen Receptor (AR), respectively. This research opens new horizons in PROTAC technology and lays a solid foundation for the next wave of therapeutic applications.