mtCI modulator C273 is a selective, brain-penetrant, orally bioavailable small molecule modulator/ weak inhibitor of mitochondrial complex I (mtCI) with IC50 of 201.5 uM, protects against Aβ toxicity through mtCI modulation.
C273 protects MC65 Tet-Off cells from Aβ-induced toxicity with an EC50 of 14.2 nM, with no detectable cytotoxicity.
C273 is a selective, weak inhibitor (IC50=201.5 uM) of the mtCI quinone binding site, shows no detectable inhibition of complexes II, III, or IV, confirming selectivity for mtCI.
C273 engages the Q site of mtCI and that its weak inhibition of mtCI is required for protection against Aβ toxicity.
C273 activates AMPK-centered neuroprotective signaling in the brain, increases phosphorylation of AMPKα and phosphorylation of ULK1 at Ser555.
C273 activates AMPK-dependent mitochondrial stress signaling and neuroprotective pathways, mitigates oxidative stress and inflammatory signaling.
C273 activates target engagement biomarkers in PBMCs and reduce Aβ and pTau in human LOAD organoids, reduces Aβ and p-Tau levels in patient-derived LOAD cerebral organoids.