Deubiquitinates (DUBs) are an essential yet understudied class of druggable enzymes. The DUB family consists of approximately 100 enzymes consisting of six subfamilies. One DUB subfamily is the ubiquitin c-terminal hydrolase family which hydrolyze c-terminal adducts from ubiquitin. Ubiquitin c-terminal hydrolase L1 (UCHL1) is a cysteine protease in the UCH family that under normal physiological conditions is almost exclusively localized to the central nervous system (CNS) and comprises between 1-5% of total soluble protein in the CNS. In the periphery, overexpression of UCHL1 is linked to aggressive forms of cancer such as triple negative breast cancer and ovarian cancer. UCHL1 has also been linked to other chronic disease states including neurodegenerative and fibrotic diseases. We have developed small. molecule probes to pharmacologically validate UCHL1 as a therapeutic target to treat these various diseases using enzymatic screening, activity-based protein profiling, click chemistry and <i>in vivo </i>assays. Here, we report the discovery of novel, covalent UCHL1 inhibitors with selectivity over closely related deubiquitinates. We have determined X-ray crystal structures (&lt;2A) of these small molecules bound to UCHL1 beginning our structure-based drug design campaign in efforts of developing more potent, selective inhibitors of UCHL1. The structural information from our lead-compound bound to UCHL1 led to the development of a novel chemical probe, UCH0061, to identify and quantify the protein labeling <i>in vivo</i>. Finally, we have demonstrated that these UCHL1 inhibitors have efficacy and selectivity in cellular models of triple negative breast cancer.

Discovery and development of novel covalent inhibitors toward ubiquitin C-terminal hydrolase L1

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ACS Fall 2022

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