ACI-16664 is an orally available brain penetrant tau aggregation inhibitor with IC50 of 0.27 uM, selectively binds and destabilizes pathological β sheets in tau aggregates.
ACI-16664 eliminates pathological tau beta sheets, inhibits aggregation, and blocks tau seeding and toxicity in vitro.
ACI-16664 reduces preformed hTau 2N4R aggregates seeded by insoluble tau filaments from AD brains (AD tau PHFs; IC50 = 0.16 uM) instead of heparin.
ACI‐16664 both disrupts pre‐existing aggregates and also prevents the formation of new pathological tau β‐sheet structures.
ACI‐16664 binds to heparin‐induced hTau 2N4R aggregates with an apparent Kd of 48 ± 9 nM and has no detectable binding to hTau 2N4R.
ACI‐16664 inhibits tau seeding and toxicity in cortical neuron culturesmonomers.
ACI‐16664 inhibits the aggregation induced by insoluble and soluble AD brain tau seeds in rat cortical neurons.
ACI‐16664 broadly reduces pathological tau species, including soluble HMW aggregates and neurofibrillary tangles, and prevents neuronal loss, synaptic degeneration, and cortical atrophy in vivo.