Open AccessEvaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease
Author(s) -
Andrew J. Stott,
Michel Maillard,
Vahri Beaumont,
D. T. C. Allcock,
Omar Aziz,
Alexander H. Borchers,
Wesley Blackaby,
Perla Breccia,
Gillian Creighton-Gutteridge,
Alan F. Haughan,
Rebecca E. Jarvis,
Christopher A. Luckhurst,
Kim L. Matthews,
George McAllister,
Scott J. Pollack,
Elizabeth A. Saville-Stones,
Amanda J. Van de Poël,
Huw D. Vater,
Julie Vann,
Rachel Williams,
Devon Yates,
Ignacio Muñoz-Sanjuán,
Celia Dominguez
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00532
Subject(s) - in vivo , histone deacetylase , acetylation , pharmacology , pharmacodynamics , trifluoromethyl , chemistry , in vitro , oxadiazole , pharmacokinetics , medicine , biochemistry , histone , biology , organic chemistry , alkyl , gene , microbiology and biotechnology
Using an iterative structure-activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12 ) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC 50 , using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington's disease.