{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Johnson FD"],"funding":["Intramural NIH HHS","NCI NIH HHS"],"pagination":["110343"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8904132"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["38(6)"],"pubmed_abstract":["Phenotype-based screening can identify small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here, we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we use thermal proteome profiling (TPP) and uncover the disulfide reductases GSR and TXNRD1 as targets. We confirm through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knocko"],"journal":["Cell reports"],"pubmed_title":["Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells."],"pmcid":["PMC8904132"],"funding_grant_id":["P30 CA008748","Z99 CA999999"],"pubmed_authors":["Lockwood WW","Shi R","Becker K","Forcina GC","de Rappard-Yuswack G","Ferrarone J","Morin GB","Somwar R","Munuganti R","Sorensen PH","Spencer Miko SE","Sihota T","Lu D","Farnsworth DA","Cheng GSW","Varmus H","Johnson FD","Luu J","Jansen S","Guha U","Nagelberg A","Zhang X","Dixon SJ","Liu A","Djaballah H","Brandstadter C"],"additional_accession":[]},"is_claimable":false,"name":"Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells.","description":"Phenotype-based screening can identify small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here, we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we use thermal proteome profiling (TPP) and uncover the disulfide reductases GSR and TXNRD1 as targets. We confirm through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knocko","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Feb","modification":"2026-05-31T19:48:33.914Z","creation":"2024-10-18T05:48:36.865Z"},"accession":"S-EPMC8904132","cross_references":{"pubmed":["35139387"],"doi":["10.1016/j.celrep.2022.110343"]}}