Objective: To develop small molecule therapeutics for PD that inhibit production of toxic α-synuclein oligomers and reduce aggregate formation, targeting the molecular mechanisms at the source of α-synuclein aggregation.

Background: The oligomeric forms of α-synuclein bind to membranes, receptors and organelles, disrupt metabolic and neuronal functional pathways causing dysfunction and neurotoxicity. These oligomers defy conventional drug discovery approaches, so we harness biophysics-based analytics to target the production of these fleeting intermediates with high precision.  More specifically, we target two mechanisms that are at the source of oligomer production: (i) primary nucleation, which is catalysed by lipid membranes, and (ii) secondary nucleation which is catalysed by α-synuclein aggregates.

Method: Precision in vitro protein aggregation assays using monomeric recombinant human α-synuclein along with advanced biophysics-based analytics were used to profile the activity of small molecule compounds, along with a range of cellular and in vivo models, including iPSC-derived dopaminergic neurons, and the M83 transgenic mouse model. We have leveraged a variety of oligomer and aggregate biomarker technologies to measure both target engagement and disease progression.

Results: Our compounds inhibited both mechanisms of α-synuclein oligomer formation with precision, inhibiting catalytic sites on the fibrils with low stoichiometry, significantly reducing oligomers and aggregates. Lead optimisation delivered enhanced potency, oral pharmacokinetics and brain penetration. First generation inhibitors demonstrated efficacy in both cell and mouse models, reducing oligomers and in turn aggregates. While second generation inhibitors were even more potent at these source mechanisms and demonstrated dramatic efficacy in aggressive seeded models (cell and mouse).

Conclusion: Our small molecule inhibitors of α-synuclein oligomer generation delivered robust effects in vitro, and in both cellular and in vivo models, demonstrating potent inhibition of oligomer production and aggregate formation. We are advancing these first-in-class, small molecule, oligomer inhibitors for the treatment of PD initially, along with oligomer biomarker technology to measure both target engagement and the impact of oligomer inhibition with disease progression in human clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/small-molecule-inhibitors-for-precise-inhibition-of-%ce%b1-synuclein-oligomer-generation-in-parkinsons-disease-pd/