Development of the first non-hydroxamate selective HDAC6 degraders

Tim Keuler; Beate König; Nico Bückreiß; Fabian B. Kraft; Philipp König; Linda Schäker-Hübner; Christian Steinebach; Gerd Bendas; Michael Gütschow; Finn K. Hansen

doi:10.1039/D2CC03712B

Development of the first non-hydroxamate selective HDAC6 degraders†

Tim Keuler,‡^a Beate König,‡^a Nico Bückreiß,‡^a Fabian B. Kraft,^a Philipp König,^a Linda Schäker-Hübner,

^a Christian Steinebach,

^a Gerd Bendas,

*^a Michael Gütschow

*^a and Finn K. Hansen

*^a

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* Corresponding authors

^a Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, Germany
E-mail: gbendas@uni-bonn.de, guetschow@uni-bonn.de, finn.hansen@uni-bonn.de

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.

Chemical Communications

Development of the first non-hydroxamate selective HDAC6 degraders†

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