Evaluation Of 5-(Trifluoromethyl)-1,2,4-Oxadiazole-Based Class Ila Hdac Inhibitors For Huntington'S Disease

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 Ha histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class Ha 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/Hb deacetylation EC50, 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/Hb cellular activity. Applying the same relationship to class Ha HDAC inhibition, we estimated the compound 12 dose required to inhibit class Ha HDAC activity, for use in predinical models of Huntington's disease.