This project will focus on the development of small molecule therapeutics to treat Parkinson’s disease by advancing lead compounds that modulate protein chaperones. Protein chaperones are proteins that guide the correct protein folding in cells and also function as the cellular quality control mechanism for correct protein folding. Chaperone’s compounds work by stimulating HSF1, a key regulator of protein chaperones, to restore normal protein balance in diseased neurons.
Chaperone Therapeutics will optimize its lead series compounds for bioavailability, pharmacological suitability and target efficacy. Compounds will be resynthesized and then expanded in an iterative hit to lead program guided by activity in Chaperone’s proprietary cell assays as well as in pharmaceutical suitability models. At least one lead series will be advanced to a stage where compounds are ready to be tested in cellular and preclinical models of Parkinson’s disease. Ultimately, the primary goal of the project outlined here is to produce a lead compound for drug development against Parkinson ’s disease. These compounds will also provide useful research tools to interrogate the role of HSPs in Parkinsons and other neurological diseases.
Relevance to Treatment of Parkinson’s Disease:
Recent evidence in cellular and preclinical model systems strongly supports the hypothesis that protein chaperones act both independently and cooperatively to ameliorate biochemical hallmarks and symptoms of Parkinson’s disease. For example, in mammalian cell culture, mouse or fruit models of alpha-synuclein toxicity, expression of protein chaperones significantly suppresses protein aggregation, increase protein solubility and turnover and ameliorate neuronal loss. Given the potential therapeutic role of elevated protein chaperone levels in ameliorating alpha synuclein aggregation and enhancing neuronal survival, small molecule-mediated activation of human HSF1 is a promising avenue for therapeutic intervention in Parkinson’s disease.
Treatments developed from this program would have the potential to not only prevent the progression of neuronal cell death, but to stimulate cell repair. This raises the prospect that some alpha-synuclein caused cell toxicity could also be reversed. If successful, this project will yield a small molecule drug lead against a new and exciting target for the treatment of Parkinson’s disease.
Chaperone Therapeutics is developing small molecules to treat Parkinson’s disease by increasing the level of naturally occurring proteins that regulate improperly folded or damaged proteins in cells. With the generous funding provided by the Michael J Fox Foundation we have been able to identify promising compounds that can be developed as drugs for the treatment of Parkinson’s disease by this novel approach.