KEAP1directed

KEAP1directed refers to research strategies and therapeutic approaches that target the KEAP1 protein to modulate the NRF2-dependent oxidative stress response. KEAP1 is a substrate adaptor for the Cul3-Rbx1 E3 ubiquitin ligase that binds NRF2 and promotes its ubiquitination and degradation. Under stress, electrophiles and oxidants modify KEAP1 cysteine residues, diminishing NRF2 ubiquitination and allowing NRF2 to accumulate and translocate to the nucleus to activate antioxidant genes. KEAP1-directed strategies aim to influence this pathway by: (1) inhibiting KEAP1 function to stabilize NRF2, (2) disrupting the KEAP1-NRF2 protein–protein interaction, or (3) degrading KEAP1 itself using targeted protein degradation approaches.

Approaches include covalent inhibitors that modify KEAP1 cysteines, non-covalent inhibitors that block NRF2 binding, peptides or small molecules that disrupt the interface, and PROTACs or molecular glues designed to reduce KEAP1 levels. These strategies are explored for conditions where boosting NRF2 activity could be protective, such as neurodegenerative diseases, inflammatory disorders, and some metabolic or ischemic injuries, as well as certain cancers where NRF2 activity may confer chemoresistance.

Clinical development of KEAP1-directed therapies is ongoing, with several compounds in preclinical or early clinical stages. Challenges include achieving tissue-specific activation, avoiding unwanted chronic NRF2 activation that may promote tumorigenesis, and managing potential off-target effects. KEAP1directed research remains an active area in redox biology and drug discovery.