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Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Open accessAbstract
The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. 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 map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
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“The authors discovered compounds that bind to a ligandable cysteine on the nuclear receptor NR0B1, which is regulated by NRF2, a substrate of KEAP1 (ref.181).”
From Advances in covalent drug discovery (2022) · cites this paper as [181]
In the citing paper
“cysteine reactivity and ligandable sites were mapped in mutant Kelch-like ECH-associated protein 1 (KEAP1) and compared with those in wild-type KEAP1 NSCLC lines.”
From Advances in covalent drug discovery (2022) · cites this paper as [181]
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“We finally observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine-26,27 or lysine-reactive28 electrophilic fragments (Fig. 3b)”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [27]
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Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer
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The rise of covalent proteolysis targeting chimeras
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NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis
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Wu, W., & Papagiannakopoulos, T. Y. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055627 · Cited by 70
“Large-scale chemical and genetic screens have identified several novel candidates that can alter the KEAP1/NRF2/CUL3 interaction or specifically inhibit NRF2 transcriptional coactivators, which should exhibit increased specificity (Bar-Peled et al. 2017, Choi et al. 2017).”
Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides
Li, F., Fu, V. X., Liu, G., Tang, T. T.-L., Konradi, A. W., Peng, X., Kemper, E. K., Cravatt, B. F., Franklin, J. M., Wu, Z., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01061-z · Cited by 63
Self-citationAssigning functionality to cysteines by base editing of cancer dependency genes
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InfluentialSelf-citationMachine learning for target discovery in drug development
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Global profiling of phosphorylation-dependent changes in cysteine reactivity
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Self-citationTMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids
Reed, A., Ware, T. B., Li, H., Bazán, J. F., & Cravatt, B. F. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01253-7 · Cited by 62
Self-citationThe Proteome‐Wide Potential for Reversible Covalency at Cysteine
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Self-citationMulti-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells
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Self-citationFunctionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization
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Self-citationTargeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target
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How the Local Environment of Functional Sites Regulates Protein Function
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Reductive stress in cancer: coming out of the shadows
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Redirecting the pioneering function of FOXA1 with covalent small molecules
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Self-citationTarget Identification of Bioactive Covalently Acting Natural Products
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Covalent binders in drug discovery
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Self-citationIdentification and selectivity profiling of small-molecule degraders via multi-omics approaches
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Self-citation
Metadata
- Authors
- Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., Chang, M. W., Kok, B. P., Zhu, Z., Ihle, N. T., Dix, M. M., Jiang, P., Hayward, M. M., Saez, E., Shaw, R. J., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Pfizer (United States) (US)
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Corresponding author
- Cravatt, Benjamin F.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 171
- Issue
- 3
- Pages
- 696-709.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5728659
- OpenAlex
- W2757007104
- Cited by
- 262
- References
- 59
- Citations by year
- 2026: 12 · 2025: 28 · 2024: 34 · 2023: 41 · 2022: 29 · 2021: 30 · 2020: 25 · 2019: 36 · 2018: 24 · 2017: 3
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (CA087660, CA132630, CA172229, CA215249-01, CA211526)
- NIH-NCI CCSG (P30 014195)
- Chapman Foundation
- Helmsley Charitable Trust
- Damon Runyon Cancer Research Foundation
- American Cancer Society
- Life Sciences Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- Nrf2, KEAP1 mutation, non-small cell lung cancer, NR0B1, orphan nuclear receptor, chemoproteomics, druggable vulnerabilities, covalent inhibitors, anchorage-independent growth, transcriptional regulation, antioxidant response
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Carcinoma, Non-Small-Cell Lung, Cysteine, Humans, Ligands, Lung Neoplasms, Proteome, Cell Line, Tumor, Gene Regulatory Networks, DAX-1 Orphan Nuclear Receptor, Transcriptome
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