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, Daniel P Flaherty
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...
March 15, 2024: Journal of Medicinal Chemistry