2. Academic Validation
  3. Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington's Disease

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington's Disease

  • ACS Med Chem Lett. 2021 Feb 11;12(3):380-388. doi: 10.1021/acsmedchemlett.0c00532.
Andrew J Stott 1,  Michel C Maillard 2,  Vahri Beaumont 2,  David Allcock 1,  Omar Aziz 1,  Alexander H Borchers 2,  Wesley Blackaby 1,  Perla Breccia 1,  Gillian Creighton-Gutteridge 1,  Alan F Haughan 1,  Rebecca E Jarvis 1,  Christopher A Luckhurst 1,  Kim L Matthews 1,  George McAllister 1,  Scott Pollack 1,  Elizabeth Saville-Stones 1,  Amanda J Van de Poël 1,  Huw D Vater 1,  Julie Vann 1,  Rachel Williams 1,  Dawn Yates 1,  Ignacio Muñoz-Sanjuán 2,  Celia Dominguez 2
Affiliations

Affiliations

  • 1 Charles River Discovery, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
  • 2 CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 700, Los Angeles, California 90045, United States.
PMID: 33738065 DOI: 10.1021/acsmedchemlett.0c00532
Abstract

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.

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