Identification, optimization, and structural elucidation of chloroacetamide scaffold as covalent inhibitors for Ubiquitin C-terminal Hydrolase L3

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Abstract The deubiquitinating enzyme, ubiquitin C-terminal hydrolase L3 (UCHL3), has been implicated as a potential therapeutic target for cancer with a role in regulating the DNA damage response pathways. While the target has been studied using genetic methods there is a lack of reliable chemical probes to selectivity target UCHL3. In this study we report hit identification and optimization of a new chemical scaffold that irreversibly inhibits UCHL3. The observed structure-activity relationships are corroborated by ligand-bound crystal structures that confirm covalent adduct formation with the catalytic cysteine of the enzyme. Finally, through gel-shift assays using a ubiquitin activity-based probe we demonstrate on-target engagement with UCHL3 in two cell lines. The work as a whole presents a comprehensive evaluation of the new scaffold that can be utilized to probe UCHL3 in different biological contexts.

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