| Autor: |
Ptacek J; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic., Snajdr I; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic., Schimer J; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic., Kutil Z; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic., Mikesova J; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic., Baranova P; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic., Havlinova B; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic., Tueckmantel W; StarWise Therapeutics LLC, University Research Park, Inc., Madison, WI 53719, USA., Majer P; Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic., Kozikowski A; StarWise Therapeutics LLC, University Research Park, Inc., Madison, WI 53719, USA.; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA., Barinka C; Institute of Biotechnology CAS, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic. |
| Abstrakt: |
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. |
