ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer

Proteolysis-targeting chimera (PROTAC)
technology has
emerged as
a potential strategy to degrade “undruggable” proteins
in recent years. Nrf2, an aberrantly activated transcription factor
in cancer, is generally considered undruggable as lacking active sites
or allosteric pockets. Here, we constructed the chimeric molecule C2, which consists of an Nrf2-binding element and a CRBN ligand,
as a first-in-class Nrf2 degrader. Surprisingly, C2 was
found to selectively degrade an Nrf2–MafG heterodimer simultaneously
via the ubiquitin–proteasome system. C2 impeded
Nrf2-ARE transcriptional activity significantly and improved the sensitivity
of NSCLC cells to ferroptosis and therapeutic drugs. The degradation
character of ARE-PROTACs suggests that the PROTAC hijacking the transcription
element of TFs could achieve co-degradation of the transcription complex.