Dual Aβ/ tau oligomer inhibitor

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TREVENTIS’ lead program concerns design of small molecule anti-oligomerization agents in tauopathy using our in silico Common Conformational Morphology (CCM) models of the protein misfolding process. Our process has involved the construction of in silico models of misfolded tau, followed by in vitro testing of the best-predicted compounds; and our experimental hit rate (>15%) is much higher than would be expected by chance. Surface plasmon resonance, TRESI-HDX and 2D NMR also provides structural support for the models.

The hit compounds identified in our innovative primary screen of oligomerization have been optimized to demonstrate potent anti-oligomer effects on misfolded proteins, either broadly or selectively from structure-activity relationships. We have made over 1,400 small molecules among several classes designed to have drug-like characteristics.

Advanced compounds in this series have demonstrated oral bioavailability and are not promiscuous inhibitors of protein-protein interactions (as shown through dynamic light scattering, tubulin assembly, etc.). Moreover, compounds in the series have shown target engagement in vivo against tau 4R as well as endpoints consistent with disease modification (e.g., behavior in the Morris Water Maze; long term potentiation) in transgenic mouse models, with nanomolar in vivo potency. This program is moving toward candidate selection in 2021.