Novel Small Molecule Inhibitors for the Treatment of Huntington’s Disease

Description:

This technology is a collection of small molecules screened for their ability to prevent or reduce the cytotoxic effects of the protein, Huntingtin. Huntington's disease is a neurodegenerative disorder due to a dominantly acting expansion of a CAG trinucleotide repeat in exon 1 of the Huntington (HTT) gene resulting in production of the altered (mutant) protein Huntingtin, which has a long chain of polyglutamine (poly Q) attached to the exon 1 encoded protein sequence. Clinical and statistical analyses have shown that an increased number of poly Q repetition correlates with the probability of developing the disease, with 36 to 40 being the accepted cut off number for developing the disorder with high probability. It is known that poly Q repetitions impact the physical properties of Huntingtin and cause it to produce aggregates that precipitate and form inclusion bodies, which are toxic to the neuronal cells. The compounds of this invention have been screened multiply in a neuronal cell model of Huntington’s disease containing an HTT with an expanded repeat in exon 1 of 103 Qs for their ability to inhibit cytotoxicity and protein aggregation.