Development of an aggregation inhibitor targeting alpha-synuclein pathology.

Background:
▪ Alpha-synuclein (a-syn) aggregation is a key pathological driver of several neurodegenerative disorders and a common co-pathology in Alzheimer’s disease where it is associated with exacerbated cognitive decline
▪ We aim to discover cell-permeable, orally bioavailable and brain penetrant small molecules that inhibit aggregation and intracellular accumulation of pathological a-syn
Results:
▪ Identified CNS-penetrant, a-syn aggregation inhibitors with nanomolar potency for inhibiting intracellular a-syn aggregate accumulation
▪ Robust effects observed even in post-seeding treatment paradigms thanks to intracellular targeting
▪ Reduced seeding-competent a-syn pathology in the Tg hPFF mouse model with significant neuroprotective effects supporting disease-modifying potential
▪ Shared binding site with PET tracer ACI-12589 supports translational biomarker and clinical development strategies

Conclusions
▪ Discovery of highly potent, brain-penetrant a-syn aggregation inhibitors
▪ Blockade of intracellular aggregation and intercellular propagation of a-syn pathology to slow disease
progression
▪ Neuroprotective effects in vivo support disease-modifying potential of a-syn Morphomers^®
▪ Therapeutic-diagnostic synergy enables optimal translation and accelerated development