2. Academic Validation
  3. Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1

Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1

  • J Med Chem. 2024 Mar 28;67(6):4496-4524. doi: 10.1021/acs.jmedchem.3c01661.
Ryan D Imhoff 1 2,  Rishi Patel 3,  Muhammad Hassan Safdar 1,  Hannah B L Jones 4,  Adan Pinto-Fernandez 4 5,  Iolanda Vendrell 4 5,  Hao Chen 1,  Christine S Muli 1,  Aaron D Krabill 1,  Benedikt M Kessler 4 5,  Michael K Wendt 1 2 6,  Chittaranjan Das 2 3 6,  Daniel P Flaherty 1 2 6
Affiliations

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.
  • 3 Department of Chemistry, College of Science, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4 Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, Oxford OX3 7FZ, U.K.
  • 5 Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, U.K.
  • 6 Purdue Institute for Cancer Research, West Lafayette, Indiana 47907, United States.
PMID: 38488146 DOI: 10.1021/acs.jmedchem.3c01661
Abstract

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.

Figures
Products