KEAP1/NRF2 as a druggable target

Nuclear factor erythroid 2-related 2 (NRF2; encoded by NFE2L2) is an inducible transcription that regulates the expression of a large network genes encoding proteins with cytoprotective functions. NRF2 also has role in maintenance mitochondrial and protein homeostasis, its activation allows adaptation to numerous types cellular stress. principally regulated at stability level three main ubiquitin ligase systems, which regulation Kelch-like ECH-associated 1 (KEAP1), substrate adaptor for Cul3/Rbx1-based ligase, best understood. KEAP1 multi-functional and, addition being adaptor, it sensor electrophiles oxidants. Pharmacological inactivation protective effects animal models human disease, now widely recognized as drug target, particularly chronic diseases, where oxidative stress inflammation underlie pathogenesis. Many compounds target have been developed, including bind covalently cysteine sensors KEAP1, non-electrophilic protein-protein interaction inhibitors Kelch domain disrupting NRF2, most recently, heterobifunctional proteolysistargeting chimeras (PROTACs) promote proteasomal degradation KEAP1. The development KEAP1-targeting led entry two compounds, dimethyl fumarate (BG-12, Tecfidera®) RTA-408 (omaveloxolone, SKYCLARYS®), clinical practice. In 2013, was licenced first oral first-line therapy relapsingremitting multiple sclerosis used treatment moderate-to-severe plaque psoriasis. February 2023, omaveloxolone approved United States Food Drug Administration only patients Friedreich's ataxia.