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New Small Molecule Inhibiting Agents of Alpha-Synuclein & Lewy Body Formation as Disease-Modifying Treatments for Parkinson's Disease

Parkinson's Disease is pathologically characterized by the presence and accumulation of a protein known as alpha-synuclein. Mutations in alpha-synuclein have been directly linked to PD, and alpha-synuclein clumping and persistence in dopamine-containing neurons is associated with loss of dopamine-producing cells in the brains of people with PD. Inhibition or disruption/elimination of alpha-synuclein aggregation in dopamine-producing neurons is an important therapeutic target for the treatment of PD and related disorders.

During the last six years, ProteoTech Inc (ProteoTech), a privately held drug discovery and development company led by founder and Chief Scientific Officer Dr. Alan Snow, has been working on the development of disease-modifying small-molecule therapeutics for the treatment of Alzheimer's and PD. Dr. Snow is a world-recognized authority on amyloid and Alzheimer's disease research, and was formerly a Research Associate Professor at the University of Washington in Seattle.

ProteoTech has been developing Exebryl(TM)-1, a disease-modifying small molecule therapeutic for Alzheimer's disease that is already in late-pre-clinical development and has been shown in animal models to markedly reduce/cause a clearance of brain amyloid deposition in old animals (by 50 to 80 percent), and cause marked improvements/reversal in memory impairments (by approximately 70 percent), following only three months of peripheral administration.From the design of more than 250 analogs from this original class of compounds, ProteoTech scientists have discovered that select small-molecule analogs markedly and specifically inhibit and disrupt alpha-synuclein from clumping and forming aggregates.

In this 3.5-year project, ProteoTech and some of the world's leading scientists in amyloid, Alzheimer's and Parkinson's disease research will further identify and develop novel small-molecule disease-modifying compounds that can penetrate the brain and cause a clearance/disruption of neuronal alpha-synuclein aggregates, as well as inhibit Lewy body formation, a characteristic brain hallmark of PD.

Specific compounds will be tested in cell-based assays in collaboration with Dr. Benjamin Wolozin, a leading Parkinson's researcher at Boston University. Compounds will be optimized for blood-brain-barrier penetration, phamacokinetics, oral bioavailability and non-toxicity in collaboration with 2 leading organic chemists, Dr. Anil Kumar, CEO of MedChem Source, LLC, and Dr. Manfred Weigele, co-founder of Ariad Pharmaceuticals and former Group Director of Chemistry Research at Hoffman-La Roche. Further testing using sophisticated biophysical assays will be implemented in collaboration with Dr. Daniel Kirschner at Boston College, a leading amyloid researcher and biophysicist who studies the abnormal assembly of proteins such as those found in brains of Alzheimer's and PD patients. The efficacy of lead compounds will then be tested in relevant animal models of PD for reduction of brain alpha-synuclein aggregation and improvement in motor abnormalities, in collaboration with Dr. Eliezer Masliah and his group at University of California-San Diego. Dr. Masliah is a world authority in Alzheimer's and Parkinson's disease and has developed some of the most innovative transgenic animal models to study Parkinson's disease for the identification of new drug treatments. By the beginning of year three of this project, the world-class team of researchers is anticipated to have identified a new small molecule therapeutic (and back-up compound) that in a relevant PD animal model will have the ability to inhibit/retard and/or cause clearance of aggregated/fibrillar alpha-synuclein, as well as cause marked improvements in motor deficits.

By the end of the 3.5 years of this project, it is anticipated that the team will have identified a clinical candidate that should be close to formal toxicity testing prior to the filing of an Investigative New Drug (IND) with the FDA, and the start of human clinical trials. This compound will have promise as a new breakthrough disease-modifying treatment for PD and related disorders.


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