Small‐Molecule Stimulators of NRF1 Transcriptional Activity

Abstract The transcription factor nuclear factor erythroid 2‐related factor 1 (NRF1) maintains proteostasis and promotes cellular resilience by stimulating the transcription of proteasomal subunits and a host of protective enzymes. Although NRF1 activation would likely be beneficial in a number of disease states, information regarding its ligandability and upstream regulation are lacking. Herein we report a high‐throughput chemical screen that identified selective stimulators of NRF1‐driven transcription, including unannotated inhibitors of the ubiquitin proteasome system (UPS) as well as two non‐UPS‐targeted compounds that synergistically activate NRF1 in the context of submaximal UPS inhibition. This work introduces a suite of tool molecules to study the NRF1 transcriptional response and to uncover the druggable components governing NRF1 activity in cells.