posted on 2021-02-11, 20:46authored byAndrew
J. Stott, Michel C. Maillard, Vahri Beaumont, David 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 Pollack, Elizabeth Saville-Stones, Amanda J. Van de Poël, Huw D. Vater, Julie Vann, Rachel Williams, Dawn Yates, Ignacio Muñoz-Sanjuán, Celia Dominguez
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 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/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.