Ryan D. Imhoff, Rishi Patel, Muhammad Hassan Safdar, Hannah B. L. Jones, Adan Pinto-Fernandez, Iolanda Vendrell, Hao Chen, Christine S. Muli, Aaron D. Krabill, Benedikt M. Kessler, Michael K. Wendt, Chittaranjan Das, and Daniel P. Flaherty
Journal of Medicinal Chemistry 2024
DOI: 10.1021/acs.jmedchem.3c01661
Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization.
