Date

Friday 06 Nov 2026

Time

15:15 - 15:45

Location

BW008

Supervisor

Stephan Hacker

2nd reviewer

Hermen Overkleeft

Jury

Bobby Florea

Drug discovery remains a critical area of biomedical research, driven by the ongoing need for new therapeutic options. This demand is further increased by the emergence of resistance and the persistence of targets that remain difficult to drug. Covalent drug discovery has high potential for identifying new starting points for therapeutics, but generating custom libraries of tailored covalent compounds can be a bottleneck, as synthesis and purification of compounds is a time-consuming process, typically limiting throughput to a few compounds per week per scientist. Examples of targets, which remain difficult to drug are methicillin-resistant Staphylococcus aureus and human 3-Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), which has the potential to be a target for cancer treatment. In this study, in-plate synthesis was combined with a direct-to-biology (D2B) approach, enabling rapid synthesis and direct screening of compounds in a high-throughput antibacterial activity or natural substrate assay. This strategy significantly accelerates hit discovery, allowing the synthesis and screening of several hundred compounds per week. Using this platform for HMGCS1, multiple promising chloroacetamide triazole compounds were identified with potencies in the micromolar range, along with chlorofluoroacetamide triazole compounds exhibiting potencies below 10 μM. These compounds represent promising candidates for further investigation. Two alkyne-functionalized probes were synthesized and confirmed target binding in activity-based protein profiling (ABPP) and proteomics. These probes offer potential to study the function of the protein in-depth as well as a starting point for a potential HMGCS1 drug.