NCATS-SM0225 is a small molecule VDAC ligand and inhibitor of Endoplasmic reticulum-associated degradation (ERAD) dislocation with IC50 of 1.02 uM in NHK-drGFP reporter assays, disrupts calcium homeostasis, triggers PERK-STIM1 axis-mediated degradation of ERAD complex proteins and induces cell death.
NCATS-SM0225 significantly inhibits the degradation of both null Hong Kong variant of α−1-antitrypsin (NHK) and an ER membrane substrate CD3δ.
NCATS-SM0225 significantly increases the levels of HA-ΔF508CFTR in both the ER (core-glycosylated B form) and at the cell surface (fully glycosylated mature C form).
NCATS-SM0225 increases ER protein processing, activates UPR, and induces ERAD complex destruction, induces selective degradation of HERP1, OS9, and FAM8A1 in HeLa cells.
NCATS-SM0225 selectively targets all three isoforms of VDAC (voltage-dependent anion channel).
NCATS-SM0225 directly interacts with VDAC1 (MST KD=3.13 uM) and regulates VDAC1 voltage-gating in vitro.
NCATS-SM0225 induces calcium elevation in mitochondria, ER, and cytosol, leading to HERP1 and OS9 degradation, selectively targets a subgroup of cancer cells while sparing normal cells.
NCATS-SM0225 (20 mg/kg) markedly inhibited tumor growth in A375 melanoma xenografts.
STIM1 regulates 225-induced calcium influx, and its phosphorylation mediates 225-induced ERAD complex degradation and cell death.