Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder of mid-life onset, characterized by chorea, cognitive abnormalities and progressive dementia. The underlying genetic defect is an expanded trinucleotide CAG repeat. No disease modifying therapies are available. Polyglutamine misfolding and aggregation have been implicated as plausible causes ofthe marked neurodegeneration;however, the therapeutic promise of aggregate inhibition has yet to be realized. We have identified small molecule inhibitors of polyglutamine aggregation in high throughput screening. Hit optimization in neuronal PCI 2 cells yielded two sulfobenzoic acid derivatives, 02-8 and AK-1, as potential therapeutic leads. ADMET profiling of 02-8 has been consistent with excellent drug-like properties. 02-8 inhibits polyglutamine aggregation in R6/2 mouse brain slices, while reversing the effects of neurodegeneration in a fruit fly model of HD. Further investigation shows that 02-8 is non-toxic, has favorable brain pharmacokinetics, reduces huntingtin aggregate size and number in vivo, is neuroprotective as measured by behavioral and neuropathological outcome measures, and significantly extends survival in R6/2 HD mice while reducing striatal neuron loss. 02-8 administration in the full-length knock-in 140 CAG mouse HD model show improved motor performance throughout disease progression with a significant reduction in huntingtin aggregates. Encouraged by the 02-8-mediated efficacy in HD mouse models, pharmacokinetic assays were carried out on two lead structural analogs, selected based on in silico calculations of their oral bioavailability. Both analogs have more favorable blood-brain-barrier penetration properties than 02-8, demonstrating the feasibility of significantly improving upon 02-8 and AK-1 as therapeutic leads through medicinal chemistry development. Accelerating the pace to bring drugs to clinical trials in humans is an important and achievable goal. From the studies performed in years 1-3, we will select one lead, establish GMP synthesis, and perform GLP ADMET studies during years 4 and 5, followed by an IND application by the end of year 5.

Public Health Relevance

Huntington's disease is a fatal progressive neurodegenerative disorder for which there are treatments proven to slow the disease course. We have identified novel drug-like compounds that modulate the causative abnormal protein and which are neuroprotective in HD models. Our goals in this project are to optimize these compounds, ready the most promising for clinical trials in humans by performing IND-enabling studies, and engaging the FDA with our data and plans withan IND submission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS066912-03
Application #
8338404
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Sutherland, Margaret L
Project Start
2010-09-22
Project End
2016-12-31
Budget Start
2014-09-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$1,354,422
Indirect Cost
$365,556
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tourette, Cendrine; Farina, Francesca; Vazquez-Manrique, Rafael P et al. (2014) The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 12:e1001895
Khanfar, Mohammad A; Quinti, Luisa; Wang, Hua et al. (2014) Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. Eur J Med Chem 76:414-26
Taylor, David M; Moser, Roger; Regulier, Etienne et al. (2013) MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci 33:2313-25
Choi, Soo Hyuk; Quinti, Luisa; Kazantsev, Aleksey G et al. (2012) 3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2). Bioorg Med Chem Lett 22:2789-93
Keryer, Guy; Pineda, Jose R; Liot, Geraldine et al. (2011) Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest 121:4372-82
Kim, Jinho; Bordiuk, Olivia L; Ferrante, Robert J (2011) Experimental models of HD and reflection on therapeutic strategies. Int Rev Neurobiol 98:419-81