Date

Wednesday 18 Nov 2026

Time

15:15 - 15:45

Location

BW019

Supervisor

Mario van der Stelt

2nd reviewer

Stephan Hacker

Jury

Zach Armstrong

Monoacyl glycerol lipase (MAGL) hydrolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) and is an interesting therapeutic target for neurodegenerative diseases. Instead of inhibiting MAGL, targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) oXer a viable alternative to increase 2-AG and reduce arachidonic acid (AA) levels in the central nervous system (CNS). The human body has over 600 E3 ligases, but the only reported MAGL degraders so far recruit the E3 ligase cereblon (CRBN). This thesis aimed at expanding the toolkit of MAGL degraders by identifying the optimal alkyl linker length of PROTACs that recruit the von-Hippel Lindau (VHL) E3 ligase. Two novel VHLbased degraders were synthesized and assessed for i) target binding, ii) target engagement in situ, and iii) target degradation in situ. Alkyl linkers of 8-10 carbon lengths induced the highest degradation (Dmax up to 78%), although they fell short compared to a CRBN-based positive control (Dmax up to 87%). For the CRBN-based PROTAC, a methylated negative control was synthesized and assessed in biological assays, and confirmed that MAGL degradation by the CRBN-based PROTAC depends on CRBN recruitment. These results are a first step toward optimizing MAGL PROTACs that recruit alternative E3 ligases. Future work should validate the VHL-based degraders’ mechanism with a negative control, optimize the VHL-recruiting PROTACs using linker rigidification and polar functionalities, and test degradation across diXerent cell lines.