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Development of the first non-hydroxamate selective HDAC6 degraders

24 August 2022, Version 2
Working Paper
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The targeted degradation of histone deacetylase 6 (HDAC6) by heterobifunctional degraders constitutes a promising approach to treat HDAC6-driven diseases. Previous HDAC6 selective degraders utilised a hydroxamic acid as a zinc-binding group (ZBG) which features mutagenic and genotoxic potential. Here we report the development of a new class of selective HDAC6 degraders based on a difluoromethyl-1,3,4-oxadiazole warhead as ZBG.

Keywords

PROTAC
HDAC
Degrader
cancer

Supplementary materials

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Description
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Supplementary Information
Description
Supplementary Figures, Schemes and Tables, experimental procedures, 1H NMR, 13C NMR and MS data, docking protocols
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Now Published

Development of the first non-hydroxamate selective HDAC6 degraders [opens in a new tab]
Tim Keuler, Beate König, Nico Bückreiß, Fabian B. Kraft, Philipp König, Linda Schäker-Hübner, Christian Steinebach, Gerd Bendas, Michael Gütschow, Finn K. Hansen journal article
Chemical Communications , Volume 58, Issue 79
Online publication date: 2022

Version History

Aug 24, 2022 Version 2

Version Notes

Addition of HDAC4 inhibition and degradation data, additional rescue experiments, and investigation of the hook effect.

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv-2022-3rhqf-v2
D O I: 10.26434/chemrxiv-2022-3rhqf-v2 [opens in a new tab]

Author’s competing interest statement

The author(s) have declared they have no conflict of interest with regard to this content

Ethics

The author(s) have declared ethics committee/IRB approval is not relevant to this content

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