Xueqing Nie, Pharmaceutical Sciences graduate student (Tang Research Group), will be defending her PhD research thesis:

Investigating Assay Development, Mechanism of Action, and Structural Requirements for Proteolysis Targeting Chimera (PROTAC)-Mediated Degradation

Proteolysis Targeting Chimera (PROTAC) is an emerging technology in drug discovery with the potential to tackle disease-causing proteins that cannot be easily targeted using traditional strategies. PROTACs are heterobifunctional small molecules composed of a ligand targeting E3 ubiquitin ligase, a ligand targeting protein of interest (POI) and a linker between them. They facilitate the formation of a ternary complex between E3 ligase and POI, thus inducing poly-ubiquitination and proteasomal degradation of POI.

This dissertation will focus on my efforts on assay development, structure-activity relationship (SAR) study, and structure prediction relevant to PROTAC-mediated protein degradation strategy. First, we reported a series of novel, potent and cell-permeable CRBN E3 ligase recruiters constructed on isoindolinone or 2,3-dihydro-2-oxo-1H-benzimidazole cores. By rational structure-based design, we successfully developed selective CRBN ligands that could be further employed in PROTAC degraders to minimize off-target effects. Besides, this dissertation will present our most recent work on the rapid synthesis of PROTACs under miniaturized conditions. By utilizing the highly efficient OPA-amine coupling reaction, our second-generation Rapid-TAC platform can produce sufficiently pure and stable PROTACs in a high-throughput manner. The last section of this dissertation will introduce a novel way to score in silico generated PROTAC-mediated ternary complex configurations by heating-accelerated pose departure (HAPOD) trials. This scoring method is valuable for structure-based PROTAC design in cases when the co-crystal structure of the PROTAC complex is unavailable.