Development of the first non-hydroxamate selective HDAC6 degraders

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

doi:10.26434/chemrxiv-2022-3rhqf-v2

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“…51 In the same year, we successfully incorporated the DFMO warhead into proteolysis-targeting chimeras (PROTACs) to selectively degrade HDAC6. 52 However, the mechanism by which DFMOs inhibit or degrade HDAC6 remained enigmatic. In a conference abstract published in 2022, we disclosed that a https://doi.org/10.26434/chemrxiv-2023-6kt1w-v4 ORCID: https://orcid.org/0000-0001-9765-5975 Content not peer-reviewed by ChemRxiv.…”

Section: Introductionmentioning

confidence: 99%

Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6

König,

Watson,

Reßing

et al. 2023

Preprint

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Histone deacetylase 6 (HDAC6) is an important drug target in oncology and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize a hydroxamic acid as zinc-binding group which limits the therapeutic opportunities due its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i, but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields the deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally results in an essentially irreversible inhibition of HDAC6.

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Section: Introductionmentioning

confidence: 99%