PhD defence Z. (Zefeng) Wang

Targeted protein degradation and multicomponent reactions in drug discovery

Multicomponent reaction (MCR) chemistry is a promising and useful tool for building the chemical library in a manner of high-efficiency, low-cost and mild conditions. Targeted protein degradation (TPD) as a hopeful technology has attracted much attention from academia and industry. TPD could be utilized to regulate the specific protein, which is an amazing tool for drug discovery. There are many concepts in TPD, such as molecular glues, PROTACs, and hydrophobic tagging.

In the first part of the thesis of Zefeng Wang, the MCR was utilized and integrated with automated, miniaturized synthesis to build a chemical library about the molecular glues and accelerate drug discovery. Cell-based phenotypic screening was performed to evaluate the chemical library in order to discover the active compounds.

In the second part of his thesis, the application of PROTACs and hydrophobic tagging technology were introduced and discussed. PROTACs are heterobifunctional molecules, with two ligands that bind to the target protein and E3 ligase, respectively, and a connected linker in between. In contrast, hydrophobic tagging mimics the process of misfolded or unfold proteins, leading to the protein destabilized and subsequent degradation. In this part, the compounds inducing SOS1 and 3CLpro protein degradation were designed and tested. Overall, this dissertation shows that MCR chemistry leads to diverse biologically important scaffolds in a simple and efficient manner and targeted protein degradation therapy is a significant concept in drug design and discovery.

Promotor: A.S.S. (Alexander) Dömling, Prof Dr

Copromotor: M.R. (Matthew) Groves, Prof Dr