Events

Yaxian Zhou, Pharmaceutical Sciences graduate student (Tang Research Group, will be defending her PhD research thesis:

Development and Mechanistic Investigation of Chimeric Molecules for the Degradation of Intra- and Extracellular Proteins

Targeted protein degradation (TPD) has rapidly emerged as a transformative therapeutic modality and a powerful tool for selectively depleting various protein targets. Proteolysis Targeting Chimeras (PROTACs) are the most advanced, with dozens of PROTAC molecules currently in clinical trials. However, traditional PROTAC synthesis methods are stepwise, time-consuming, and unsuitable for high-throughput screening. In this thesis, we introduce Rapid-TAC, a rapid synthesis platform employing a traceless OPA-amine coupling reaction to enables high-throughput synthesis of PROTACs for direct screening without requiring additional purification steps. Using Rapid-TAC platform, we successfully identified PROTACs targeting the androgen receptor (AR) and bromodomain-containing protein 4 (BRD4), demonstrating the feasibility and efficiency of this platform.

Complementing PROTACs, Lysosome Targeting Chimeras (LYTACs) expand TPD to include extracellular secreted and membrane-bound proteins. The first LYTACs, which recruit cation independent mannose-6-phosphate receptors (CIM6PR), can induce protein degradation across various tissues due to M6PR’s ubiquitous expression. However, this widespread expression raises concerns about on-target/off-tissue toxicity. Additionally, the complex synthesis and high multivalency required for CIM6PR ligands have hindered their broader application. To address these limitations, we developed structurally well-defined M6Pn-peptide ligands with a simplified synthesis process, demonstrated its ability to mediate internalization of soluble proteins and degradation of membrane proteins. To minimize on-target/off-tissue toxicity, we developed triantennary N-acetylgalactosamine (tri-GalNAc)-attached conjugates that interact with asialoglycoprotein receptor (ASGPR) for selective degradation of target proteins in liver cells. To broaden the scope of TPD for cancer-related targets, we developed two novel platforms: integrin-targeting chimeras (ITACs) and Folate Receptor Targeting Chimeras (FRTACs). These platforms leverage cancer-overexpressing receptors, integrin and folate receptor (FR), respectively, to specifically induce protein degradation in cancer cells. Notably, FRTACs targeting PD-L1 exhibit significant anti-tumor effects by promoting the infiltration of cytotoxic T cells into tumors. Lastly, we explored the potential of developing catalytic degraders using transferrin and its receptor (TfR). This innovative approach demonstrated the feasibility of recycling degraders to enhance
catalytic efficiency. In summary, this thesis presents advancements in TPD through innovative platforms that improve the selectivity, efficiency, and therapeutic potential of TPD strategies.