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Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany
Author to whom correspondence should be addressed.
Academic Editor: Elisa Nuti
Molecules 2021, 26(17), 5151;
Received: 5 July 2021 / Revised: 22 August 2021 / Accepted: 24 August 2021 / Published: 25 August 2021
(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators II)
Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information. View Full-Text
Keywords: histone deacetylase (HDAC); histone deacetylase inhibitors (HDACis); zinc-binding group (ZBG); non-hydroxamate histone deacetylase (HDAC); histone deacetylase inhibitors (HDACis); zinc-binding group (ZBG); non-hydroxamate
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MDPI and ACS Style

Frühauf, A.; Meyer-Almes, F.-J. Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases. Molecules 2021, 26, 5151.

AMA Style

Frühauf A, Meyer-Almes F-J. Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases. Molecules. 2021; 26(17):5151.

Chicago/Turabian Style

Frühauf, Anton, and Franz-Josef Meyer-Almes. 2021. "Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases" Molecules 26, no. 17: 5151.

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