ER-000444793 is a small molecule, non-toxic mPTP inhibitor with a mechanism of action independent of CypD inhibition. It potently and dose-dependently inhibits Ca 2+ -induced mPT. It binds CypD, a CsA/CypD homogenous time-resolved fluorescence (HTRF) assay is used to study compound binding. Both CsA and SfA dose-dependently decrease HTRF signal, suggesting displacement of labelled CsA from rhCypD protein (CsA IC 50 =23 nM and SfA IC 50 = 5 nM). In contrast, ER-000444793 has no effect up to a concentration of 50 μM, indicating lack of displacement of labelled -CsA from rhCypD protein. Together, these data suggest the mechanism of it in delaying mPT is independent of CypD functional inhibition.
