Date

Thursday 20 Aug 2026

Time

15:15 - 15:45

Location

BW019

Supervisor

Stephan Hacker

2nd reviewer

Hermen Overkleeft

Jury

Sebastian Geibel

Targeted covalent inhibitors (TCIs) can irreversibly bind to proteins, providing enhanced potency, selectivity, and durability of inhibition. Therefore, they are increasingly important in drug discovery, e.g. for treating cancer and combating antimicrobial resistance. The development of new reactive groups (so-called warheads) for TCIs remains essential to expand their target scope, improve their safety profile and enable tunability of their reactivity. To expand the landscape of effective and safe covalent warheads for TCIs, we investigated several chemotypes using a combination of reactivity assays, gel-based activity-based protein profiling, and chemoproteomics. We especially explored chiral sulfonylated 3-hydroxypyrrolidones that allow for tunable reactivity by varying the sulfonate substituent. Chemoproteomics demonstrated that around 6% of all labeled proteins were enantioselectively targeted by this warhead indicating high tractability of the addressed binding pocket. Several interesting proteins, such as UBA2 and CDK12, were bound in their active site exemplifying the applicability and relevance of this warhead class. Therefore, these chiral, tunable warheads hold high potential to serve as reactive groups for the development of TCIs.