Excessive oxidative stress and related inflammation are pathological factors for the development and progress of non-alcoholic steatohepatitis (NASH), kidney diseases, and inflammatory bowel disease (IBD). Nuclear factor erythroid 2-like 2 (NRF2) is a master regulator that activates the cellular defense system against oxidative stress, and its activation improves oxidative stress-related disease conditions. Under unstressed conditions, NRF2 is constitutively ubiquitinated via its interaction with Kelch-like ECH-associated protein 1 (KEAP1) and degraded by the proteasomal pathway, thereby limiting the NRF2-induced antioxidative effects.

We focused on the identification of a new small molecule that can specifically inhibit the interaction of NRF2 and KEAP1, which is likely an effective and safe strategy. SCO-116, identified by SCOHIA researchers, is a novel NRF2 activator that selectively inhibits the interaction of KEAP1 with NRF2. An orally available SCO-116 selectively activates NRF2 in the liver, kidney, and gut, which likely results in good efficacy and safety profiles.

The therapeutic efficacy of SCO-116 has been demonstrated in preclinical NASH and kidney disease models; hence, this drug may be effective in clinical settings. Investigational New Drug-enabling studies are ongoing in preparation for advancement to clinical development.

Indication

  • Chronic kidney disease (CKD)
  • Diabetic kidney disease (DKD)
  • Nonalcoholic steatohepatitis (NASH)
  • Other oxidative stress-related diseases
  • Antioxidant effect
SCO-116
Cytoplasm
KEAP1
NRF2

KEAP1-NRF2
interaction
inhibition

Nucleus

NRF2 activation

NASH

肝臓

Anti-fibrosis
Anti-fatty liver

CKD/DKD

腎臓

GFR increase
Anti-fibrosis

Other oxidative stress
related diseases