Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation

Silke Geurs; Dorien Clarisse; Freya Baele; Jorick Franceus; Tom Desmet; Karolien De Bosscher; Matthias D'hooghe

doi:10.1039/D2CC01550A

Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation†

Silke Geurs,^ab Dorien Clarisse,^bc Freya Baele,^a Jorick Franceus,^d Tom Desmet,^d Karolien De Bosscher^bc and Matthias D'hooghe

*^a

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* Corresponding authors

^a SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
E-mail: Matthias.Dhooghe@UGent.be

^b Translational Nuclear Receptor Research, VIB-UGent Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, FSVMII, Zwijnaarde, Belgium

^c Department of Biomolecular Medicine, Ghent University, Technologiepark-Zwijnaarde 75, FSVMII, Zwijnaarde, Belgium

^d Center for Synthetic Biology (CSB), Department of Biotechnology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium

Abstract

Non-selective inhibition of different histone deacetylase enzymes by hydroxamic acid-based drugs causes severe side effects when used as a (long-term) cancer treatment. In this work, we searched for a potent zinc-binding group able to replace the contested hydroxamic acid by employing a lean inhibitor strategy. This instructed the synthesis of a set of HDAC6-selective inhibitors containing the more desirable mercaptoacetamide moiety. Biological evaluation of these new compounds showed an IC₅₀ in the nanomolar range, dose-dependent HDAC6 inhibition in MM1.S cells and improved genotoxicity results, rendering these new inhibitors valuable hits for applications even beyond oncology.

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DOI: https://doi.org/10.1039/D2CC01550A
Article type: Communication
Submitted: 18 Mar 2022
Accepted: 19 Apr 2022
First published: 05 May 2022

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Chem. Commun., 2022,58, 6239-6242

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Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation

S. Geurs, D. Clarisse, F. Baele, J. Franceus, T. Desmet, K. De Bosscher and M. D'hooghe, Chem. Commun., 2022, 58, 6239 DOI: 10.1039/D2CC01550A

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Chemical Communications

Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation†

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Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation

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