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Small‐Molecule Stimulators of NRF1 Transcriptional Activity
Author(s) -
Iaconelli Jonathan,
Ibrahim Lara,
Chen Emily,
Hull Mitchell,
Schultz Peter G.,
Bollong Michael J.
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900487
Subject(s) - nrf1 , proteostasis , transcription factor , proteasome , microbiology and biotechnology , biology , chemistry , biochemistry , gene
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.