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O. AZIZ1, C. A. LUCKHURST1, T. HEIKKINEN2, O. KONTKANEN2, G. TOMBAUGH4, S. GELMAN5, D. YATES1, K. MATTHEWS1, R. WILLIAMS1, P. BRECCIA1, M. LAMERS1, R. JARVIS1, A. HAUGHAN1, D. FISCHER3, G. MCALLISTER1, W. BLACKABY1, A. GHAVAMI4, G. OSBORNE6, D. GOODWIN6, G. BATES6, I. MUNOZ-SANJUAN7, C. DOMINGUEZ7, L. PARK7, M. MAILLARD7, V. BEAUMONT7

1Charles River, Saffron Walden, United Kingdom; 2Charles River, Kuopio, Finland; 3Charles River, Leiden, Netherlands; 4Psychogenics Inc., Montvale, NJ; 5Psychogenics Inc., Montvale, NJ; 6UCL Inst. of Neurol., London, United Kingdom; 7CHDI Mgmt., Los Angeles, CA

Huntington’s disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a polyglutamine-encoding CAG expansion in the Huntingtin (HTT) gene. Targeting the Class IIa histone deacetylase HDAC4 appears to be a promising therapeutic strategy to treat HD. HDAC4 genetic reduction in the R6/2 HD mouse model ameliorated motor and CNS neurophysiological deficits and improved survival [1]. In addition, HDAC4 reduction delayed huntingtin (Htt) aggregation in CNS tissue from both the R6/2 and HdhQ150 full length KI mouse model of HD [1]. We have developed several chemical series of potent, selective, orally bioavailable and CNS-penetrant catalytic-site inhibitors of Class IIa HDACs [2,3], to probe whether HDAC4 inhibition can replicate the beneficial effects of HDAC4 reduction in HD models. This strategy is untested, as the deacetylase activity of Class IIa HDACs have been called into question [4]. Two structurally distinct lead series compounds have been evaluated in a battery of HD model interrogations, including R6/2 in vivo behavioral and survival endpoints and HD model ex vivo electrophysiological and molecular readouts following chronic dosing. These compounds; CHDI-00390576 and CHDI-00484077, differ as to the warhead used to engage the Zn2+ ion in the catalytic site of Class IIa HDACs (hydroxamate versus trifluoromethyloxadiazole), their ability to disrupt HDAC4:HDAC3 associations, their pharmacokinetic (PK) and pharmacodynamic (PD) properties and their selectivity over Class I/IIb HDACs. We will present the detailed PK-PD biomarker and modeling approaches used to determine appropriate chronic dosing regimens for the inhibitors, and summarize our data where we determine that selective Class IIa catalytic site inhibition fails to replicate all beneficial effects seen following HDAC4 genetic reduction in HD models. While some neurophysiological deficits, restored following HDAC4 genetic reduction, are convincingly and dose-dependently restored in HD models following treatment with either compound; we failed to significantly impact behavioral deficits. We also had no effect on Htt aggregation levels through chronic dosing. Our results suggest that blocking the catalytic site of HDAC4 is insufficient to fully recapitulate the spectrum of biological functions that HDAC4 knock-down subserves in an HD context, whilst specifically improving some aspects of HD pathophysiology. 1] Mielcarek M., et al., PLoS Biol, 2013. 11(11): p. e1001717.[2] Burli R., et al., J. Med Chem 2013. 56(24): p9934-54[3] Luckhurst C.A., et al. ACS Med Chem Lett, 2016. 7(1): p34-9 [4] Lahm A., et al. PNAS USA, 2007. 104(44): p17335-40