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

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

doi:10.3390/molecules26051227

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

Journal article

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

Aaron D Krabill, Hao Chen, Sajjad Hussain, Chad S Hewitt, Ryan D Imhoff, Christine S Muli, Chittaranjan Das, Paul J Galardy, Michael K Wendt and Daniel P Flaherty

Molecules (Basel, Switzerland), Vol.26(5), p.1227

02/25/2021

DOI: 10.3390/molecules26051227

PMCID: 7956625

PMID: 33668938

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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, , with an IC 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 a new tool to be used in the biological evaluation of UCHL1.

Antineoplastic Agents - chemical synthesis

Antineoplastic Agents - chemistry

Antineoplastic Agents - 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

Protease Inhibitors - chemistry

Protease Inhibitors - pharmacology

Structure-Activity Relationship

Ubiquitin Thiolesterase - antagonists & inhibitors

Ubiquitin Thiolesterase - metabolism

Details

Title: Subtitle: Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1
Creators: Aaron D Krabill - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
Hao Chen - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
Sajjad Hussain - Mayo Clinic
Chad S Hewitt - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
Ryan D Imhoff - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
Christine S Muli - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA
Chittaranjan Das - Purdue University West Lafayette
Paul J Galardy - Mayo Clinic
Michael K Wendt - Purdue University West Lafayette
Daniel P Flaherty - Purdue University West Lafayette
Resource Type: Journal article
Publication Details: Molecules (Basel, Switzerland), Vol.26(5), p.1227
DOI: 10.3390/molecules26051227
PMID: 33668938
PMCID: 7956625
NLM abbreviation: Molecules
ISSN: 1420-3049
eISSN: 1420-3049
Grant note: T32 GM125620 / NIGMS NIH HHS
Language: English
Date published: 02/25/2021
Academic Unit: Internal Medicine
Record Identifier: 9984459624102771

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