Figure 15. The dark side of NRF2 has led to a search for NRF2 inhibitors.

A) The first NRF2 pathway inhibitor to be revealed was all-trans retinoic acid (ATRA). However, this was not without controversy as some groups reported ATRA to be an NRF2 activator. In any case, ATRA revealed RXR-𝛼 as a negative regulator of NRF2 transcription and defined the Neh7 domain as the site of RXR-𝛼 binding. B) Brusatol is a quassinoid that inhibits the synthesis of NRF2 and is the most potent NRF2 pathway inhibitor known. Despite potential off-target effects, brusatol (Brucia javanica) has been used extensively to probe the NRF2 pathway and reveal the intricacies of the dark-side of NRF2. C) Brucein C (Brucia javanica) was found to be inactive in NRF2 pathway assays. D) Bruceantin (Brucea antidysenterica) has been shown to be more potent than brusatol at inhibiting NRF2 function. These three molecules, and others of the class, show interesting SAR related to the lipid ester. E) and F) Febrifugine (Dichroa febrifuga) and halofuginone, a semi-synthetic derivative of febrifuginone, were shown to block prolyl-tRNA synthetase, thus blocking NRF2 synthesis and confirmed some of the studies conducted by brusatol, cementing the importance of the discovery and development of an NRF2 inhibitor. G) Wogonin (Scutellaria baicalensis) has been shown to decrease NRF2 mRNA levels and to reverse chemoresistance. However, conflicting studies have shown this to be an NRF2 activating compound.