Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer. Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T., Svensson, R. U., Olucha, J., Chang, M. W., Kok, B. P., Zhou, Z., Ihle, N., Dix, M. M., Jiang, P., Hayward, M. M., Saez, E., Shaw, R. J., & Cravatt, B. F. Cell, 171(3):696–709.e23, October, 2017. ![Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex The transcription factor NRF2 is a master regulator of the cellular antioxidant response and is often genetically activated in Non-Small Cell Lung Cancers (NSCLCs) by, for instance, mutations in the interacting protein 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 was 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 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.
@article{bar-peled_chemical_2017,
title = {Chemical {Proteomics} {Identifies} {Druggable} {Vulnerabilities} in a {Genetically} {Defined} {Cancer}},
volume = {171},
issn = {0092-8674},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728659/},
doi = {10.1016/j.cell.2017.08.051},
abstract = {The transcription factor NRF2 is a master regulator of the cellular antioxidant response and is often genetically activated in Non-Small Cell Lung Cancers (NSCLCs) by, for instance, mutations in the interacting protein 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 was 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 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.},
number = {3},
urldate = {2022-01-10},
journal = {Cell},
author = {Bar-Peled, Liron and Kemper, Esther K. and Suciu, Radu M. and Vinogradova, Ekaterina V. and Backus, Keriann M. and Horning, Benjamin D. and Paul, Thomas A. and Ichu, Taka-Aki and Svensson, Robert U. and Olucha, Jose and Chang, Max W. and Kok, Bernard P. and Zhou, Zhu and Ihle, Nathan and Dix, Melissa M. and Jiang, Ping and Hayward, Matthew M. and Saez, Enrique and Shaw, Reuben J. and Cravatt, Benjamin F.},
month = oct,
year = {2017},
pmid = {28965760},
pmcid = {PMC5728659},
pages = {696--709.e23},
}
Downloads: 0
{"_id":"BppY8D5zjCAfFyabS","bibbaseid":"barpeled-kemper-suciu-vinogradova-backus-horning-paul-ichu-etal-chemicalproteomicsidentifiesdruggablevulnerabilitiesinageneticallydefinedcancer-2017","author_short":["Bar-Peled, L.","Kemper, E. K.","Suciu, R. M.","Vinogradova, E. V.","Backus, K. M.","Horning, B. D.","Paul, T. A.","Ichu, T.","Svensson, R. U.","Olucha, J.","Chang, M. W.","Kok, B. P.","Zhou, Z.","Ihle, N.","Dix, M. M.","Jiang, P.","Hayward, M. M.","Saez, E.","Shaw, R. J.","Cravatt, B. F."],"bibdata":{"bibtype":"article","type":"article","title":"Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer","volume":"171","issn":"0092-8674","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728659/","doi":"10.1016/j.cell.2017.08.051","abstract":"The transcription factor NRF2 is a master regulator of the cellular antioxidant response and is often genetically activated in Non-Small Cell Lung Cancers (NSCLCs) by, for instance, mutations in the interacting protein 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 was 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 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.","number":"3","urldate":"2022-01-10","journal":"Cell","author":[{"propositions":[],"lastnames":["Bar-Peled"],"firstnames":["Liron"],"suffixes":[]},{"propositions":[],"lastnames":["Kemper"],"firstnames":["Esther","K."],"suffixes":[]},{"propositions":[],"lastnames":["Suciu"],"firstnames":["Radu","M."],"suffixes":[]},{"propositions":[],"lastnames":["Vinogradova"],"firstnames":["Ekaterina","V."],"suffixes":[]},{"propositions":[],"lastnames":["Backus"],"firstnames":["Keriann","M."],"suffixes":[]},{"propositions":[],"lastnames":["Horning"],"firstnames":["Benjamin","D."],"suffixes":[]},{"propositions":[],"lastnames":["Paul"],"firstnames":["Thomas","A."],"suffixes":[]},{"propositions":[],"lastnames":["Ichu"],"firstnames":["Taka-Aki"],"suffixes":[]},{"propositions":[],"lastnames":["Svensson"],"firstnames":["Robert","U."],"suffixes":[]},{"propositions":[],"lastnames":["Olucha"],"firstnames":["Jose"],"suffixes":[]},{"propositions":[],"lastnames":["Chang"],"firstnames":["Max","W."],"suffixes":[]},{"propositions":[],"lastnames":["Kok"],"firstnames":["Bernard","P."],"suffixes":[]},{"propositions":[],"lastnames":["Zhou"],"firstnames":["Zhu"],"suffixes":[]},{"propositions":[],"lastnames":["Ihle"],"firstnames":["Nathan"],"suffixes":[]},{"propositions":[],"lastnames":["Dix"],"firstnames":["Melissa","M."],"suffixes":[]},{"propositions":[],"lastnames":["Jiang"],"firstnames":["Ping"],"suffixes":[]},{"propositions":[],"lastnames":["Hayward"],"firstnames":["Matthew","M."],"suffixes":[]},{"propositions":[],"lastnames":["Saez"],"firstnames":["Enrique"],"suffixes":[]},{"propositions":[],"lastnames":["Shaw"],"firstnames":["Reuben","J."],"suffixes":[]},{"propositions":[],"lastnames":["Cravatt"],"firstnames":["Benjamin","F."],"suffixes":[]}],"month":"October","year":"2017","pmid":"28965760","pmcid":"PMC5728659","pages":"696–709.e23","bibtex":"@article{bar-peled_chemical_2017,\n\ttitle = {Chemical {Proteomics} {Identifies} {Druggable} {Vulnerabilities} in a {Genetically} {Defined} {Cancer}},\n\tvolume = {171},\n\tissn = {0092-8674},\n\turl = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728659/},\n\tdoi = {10.1016/j.cell.2017.08.051},\n\tabstract = {The transcription factor NRF2 is a master regulator of the cellular antioxidant response and is often genetically activated in Non-Small Cell Lung Cancers (NSCLCs) by, for instance, mutations in the interacting protein 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 was 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 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.},\n\tnumber = {3},\n\turldate = {2022-01-10},\n\tjournal = {Cell},\n\tauthor = {Bar-Peled, Liron and Kemper, Esther K. and Suciu, Radu M. and Vinogradova, Ekaterina V. and Backus, Keriann M. and Horning, Benjamin D. and Paul, Thomas A. and Ichu, Taka-Aki and Svensson, Robert U. and Olucha, Jose and Chang, Max W. and Kok, Bernard P. and Zhou, Zhu and Ihle, Nathan and Dix, Melissa M. and Jiang, Ping and Hayward, Matthew M. and Saez, Enrique and Shaw, Reuben J. and Cravatt, Benjamin F.},\n\tmonth = oct,\n\tyear = {2017},\n\tpmid = {28965760},\n\tpmcid = {PMC5728659},\n\tpages = {696--709.e23},\n}\n\n","author_short":["Bar-Peled, L.","Kemper, E. K.","Suciu, R. M.","Vinogradova, E. V.","Backus, K. M.","Horning, B. D.","Paul, T. A.","Ichu, T.","Svensson, R. U.","Olucha, J.","Chang, M. W.","Kok, B. P.","Zhou, Z.","Ihle, N.","Dix, M. M.","Jiang, P.","Hayward, M. M.","Saez, E.","Shaw, R. J.","Cravatt, B. F."],"key":"bar-peled_chemical_2017","id":"bar-peled_chemical_2017","bibbaseid":"barpeled-kemper-suciu-vinogradova-backus-horning-paul-ichu-etal-chemicalproteomicsidentifiesdruggablevulnerabilitiesinageneticallydefinedcancer-2017","role":"author","urls":{"Paper":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728659/"},"metadata":{"authorlinks":{}},"html":""},"bibtype":"article","biburl":"https://bibbase.org/zotero/qingyuhms","dataSources":["uJZG8wcPfTAfBw67Z"],"keywords":[],"search_terms":["chemical","proteomics","identifies","druggable","vulnerabilities","genetically","defined","cancer","bar-peled","kemper","suciu","vinogradova","backus","horning","paul","ichu","svensson","olucha","chang","kok","zhou","ihle","dix","jiang","hayward","saez","shaw","cravatt"],"title":"Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer","year":2017}