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.
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