Description:

The Department of Biochemistry and Molecular Genetics and Center for Synthetic Biology welcomes faculty candidate:

Liron Bar-Peled, PhD
Post-Doctoral Fellow, Chemical Physiology
The Scripps Research Institute, California

The bZIP transcription factor NRF2 is a master regulator of the cellular antioxidant response and often genetically deregulated in Non-Small Cell Lung Cancers (NSCLCs). While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to dually map redox sensitive and druggable proteins unique to NRF2-activated cancers which are required for the anchorage-independent growth of these cells. Principal among these was NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of NRF2-activated cancer cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain and demonstrate that these compounds disrupt NR0B1 complexes and impair NRF2-dependent cancer cell growth. Our findings thus designate NR0B1 as a druggable, transcriptional regulator that supports NRF2-activated lung cancers.