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Open AccessArticle

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

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Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
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Division of Pediatric Hematology-Oncology, Mayo Clinic, 200 First St. Guggenheim 15, Rochester, MN 55905, USA
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Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First St. Guggenheim 15, Rochester, MN 55905, USA
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Department of Chemistry, College of Science, 560 Oval Dr., West Lafayette, IN 47907, USA
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Purdue Center for Cancer Research, Hanson Life Sciences Research Building, 201 University St., West Lafayette, IN 47907, USA
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Purdue Institute for Drug Discovery, 720 Clinic Ln., West Lafayette, IN 47907, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Steven Fletcher
Molecules 2021, 26(5), 1227; https://doi.org/10.3390/molecules26051227
Received: 12 January 2021 / Revised: 12 February 2021 / Accepted: 19 February 2021 / Published: 25 February 2021
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. View Full-Text
Keywords: covalent inhibitors; fluoromethylketones; UCHL1 inhibitors; deubiquitinases covalent inhibitors; fluoromethylketones; UCHL1 inhibitors; deubiquitinases
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MDPI and ACS Style

Krabill, A.D.; Chen, H.; Hussain, S.; Hewitt, C.S.; Imhoff, R.D.; Muli, C.S.; Das, C.; Galardy, P.J.; Wendt, M.K.; Flaherty, D.P. Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1. Molecules 2021, 26, 1227. https://doi.org/10.3390/molecules26051227

AMA Style

Krabill AD, Chen H, Hussain S, Hewitt CS, Imhoff RD, Muli CS, Das C, Galardy PJ, Wendt MK, Flaherty DP. Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1. Molecules. 2021; 26(5):1227. https://doi.org/10.3390/molecules26051227

Chicago/Turabian Style

Krabill, Aaron D.; Chen, Hao; Hussain, Sajjad; Hewitt, Chad S.; Imhoff, Ryan D.; Muli, Christine S.; Das, Chittaranjan; Galardy, Paul J.; Wendt, Michael K.; Flaherty, Daniel P. 2021. "Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1" Molecules 26, no. 5: 1227. https://doi.org/10.3390/molecules26051227

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