KI696

KI696 is a selective KEAP1/NRF2 protein-protein interaction inhibitor with a human K_d value of 1.3 nM. KI696 acts by competitively occupying the NRF2-binding pocket of the KEAP1 Kelch domain. KI696 blocks KEAP1-mediated ubiquitination and degradation of NRF2, promotes the translocation of NRF2 to the nucleus, activates the expression of downstream antioxidant genes, increases intracellular glutathione levels, and alleviates oxidative stress-induced cell damage and inflammatory cell infiltration in the lungs. KI696 reduces ozone-induced pulmonary oxidative damage and inflammatory cell accumulation in rats, and upregulates pulmonary antioxidant genes. KI696 can be used in research related to chronic obstructive pulmonary disease, oxidative stress and inflammation^[1]. In Vitro:KI696 (compound 7) potently inhibits the interaction between the human KEAP1 Kelch domain and NRF2 peptide in cell-free fluorescence polarization (FP) assays; it binds tightly to the human KEAP1 Kelch domain in cell-free isothermal titration calorimetry (ITC) assays, with a K_d value of 1.3 nM^[1].
KI696 exhibits selective off-target properties and shows no cytotoxicity against BEAS-2B human lung epithelial cells at concentrations up to 10 μM^[1].
KI696 promotes the nuclear translocation of NRF2 in a concentration-dependent manner after 6 h treatment on NHBE cells^[1].
KI696 upregulates the expression of NRF2-dependent genes (NQO1 and GCLM) in NHBE cells in an NRF2-dependent manner; it induces NQO1 enzymatic activity in an NRF2-dependent manner; it increases NQO1 enzymatic activity in a concentration-dependent manner in human lung epithelial BEAS-2B cells, with an EC₅₀ of 12 nM after 48 h of treatment^[1].
KI696 (0.0003-1 μM; 18 h) increases intracellular glutathione levels in a concentration-dependent manner and inhibits tBHP-induced glutathione depletion in NHBE cells after 18 h of pretreatment^[1].
KI696 (incubated for 6 h) upregulates the expression of NRF2-regulated genes (NQO1, TXNRD1, GCLM and HO-1) in COPD-derived bronchial epithelial ALI cells in a concentration-dependent manner, with an EC₅₀ of 22 nM for NQO1 after 6 h of treatment^[1]. In Vivo:KI696 (5-50 µmol/kg; i.v.; infusion over 6 hours) dose-dependently activates the NRF2 pathway in the lungs of healthy male Han Wistar rats, with an average EC₅₀ of 36.4 µmol/kg for induction of NRF2-regulated gene expression^[1].
KI696 (10-50 µmol/kg; i.v.; infusion over 6 hours; 24 hours prior to ozone exposure) attenuates ozone-induced pulmonary inflammation and restores depleted lung GSH levels in male Han Wistar rats^[1].