Selectivity of Hydroxamate- and Difluoromethyloxadiazole-Based Inhibitors of Histone Deacetylase 6 In Vitro and in Cells

0571548 - BTÚ 2024 RIV CH eng J - Journal Article
Ptáček, Jakub - Šnajdr, Ivan - Schimer, Jiří - Kutil, Zsofia - Mikesova, Jana - Baranová, Petra - Havlínová, Barbora - Tueckmantel, W. - Majer, Pavel - Kozikowski, A. - Bařinka, Cyril
Selectivity of Hydroxamate- and Difluoromethyloxadiazole-Based Inhibitors of Histone Deacetylase 6 In Vitro and in Cells.
International Journal of Molecular Sciences. Roč. 24, č. 5 (2023), č. článku 4720. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GA21-31806S; GA MŠMT LX22NPO5102
Institutional support: RVO:86652036 ; RVO:61388963
Keywords : metallohydrolase * histone deacetylase * inhibitor profiling * tubulin * histone acetylation * nanoBRET
OECD category: Biochemistry and molecular biology
Impact factor: 5.6, year: 2022
Method of publishing: Open access
https://www.mdpi.com/1422-0067/24/5/4720

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family of enzymes due to its complex domain organization and cytosolic localization. Experimental data point toward the therapeutic use of HDAC6-selective inhibitors (HDAC6is) for use in both neurological and psychiatric disorders. In this article, we provide side-by-side comparisons of hydroxamate-based HDAC6is frequently used in the field and a novel HDAC6 inhibitor containing the difluoromethyl-1,3,4-oxadiazole function as an alternative zinc-binding group (compound 7). In vitro isotype selectivity screening uncovered HDAC10 as a primary off-target for the hydroxamate-based HDAC6is, while compound 7 features exquisite 10,000-fold selectivity over all other HDAC isoforms. Complementary cell-based assays using tubulin acetylation as a surrogate readout revealed approximately 100-fold lower apparent potency for all compounds. Finally, the limited selectivity of a number of these HDAC6is is shown to be linked to cytotoxicity in RPMI-8226 cells. Our results clearly show that off-target effects of HDAC6is must be considered before attributing observed physiological readouts solely to HDAC6 inhibition. Moreover, given their unparalleled specificity, the oxadiazole-based inhibitors would best be employed either as research tools in further probing HDAC6 biology or as leads in the development of truly HDAC6-specific compounds in the treatment of human disease states.
Permanent Link: https://hdl.handle.net/11104/0342903