Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1.

Abstract

The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 µM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.

• Authors: Aaron D Krabill, Hao Chen, Sajjad Hussain, Chad S Hewitt, Ryan D Imhoff, Christine S Muli, Chittaranjan Das, Paul J Galardy, Michael K Wendt, Daniel P Flaherty
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 5 (Feb 25 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 33668938 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Protease Inhibitors
• UCHL1 protein, human
• Ubiquitin Thiolesterase

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Models, Molecular
• Molecular Structure
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Ubiquitin Thiolesterase (antagonists & inhibitors, metabolism)