biostudies-literatureTakahashi MNIA NIH HHSNCI NIH HHSNIAMS NIH HHSNIGMS NIH HHS2536-2556.e30https://www.ebi.ac.uk/biostudies/studies/S-EPMC11143475biostudies-literatureUnknown187(10)Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA bindinCellDrugMap: A quantitative pan-cancer analysis of cysteine ligandability.PMC11143475R01 CA137008P01 CA163222R35 GM146933R01 AR043369R21 AG083413R21 CA256082R01 CA129933R00 CA215249K99 CA215249R01 CA222871R37 CA260062R35 GM153476K08 CA226391R37 CA245523DP2 GM137494R01 CA164273R01 CA285415R01 AR072304Alghali ASOTsou CCDomingues ACShi LFang JBoland GMZhang JSuva MLBussema LHaber DAGe MZhang SYoda SDong RAcker ALawrence MSHata ANOjeda SNeil JRPatel HBrooijmans NVillanueva ARivera MNChen NDubash TJenkins RWWakefield FNClark SETien PCMartin BRMurrey HEKarakyriakou BLiau BBVordermark KLawless ARichter MRubio KKhandelwal NHarrison DKoglin ASGohar MKryukov GHara TDurr BRNguyen LPHosp TPopoola GTakahashi MBardeesy NMLazarov MJSade-Feldman MWhite RDFisher DEKastanos JRachmin IChong HBHilbert BYang TYRasmussen MQMakram FMaynard MBar-Peled LHarry SHealy AMaheswaran SGriesshaber HAssaad JOh EOtt CJvan den Ouweland SReeves SMfalseDrugMap: A quantitative pan-cancer analysis of cysteine ligandability.Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA bindin2024-01-01T00:00:00Z2024 May2026-06-01T05:23:26.572Z2026-04-08T09:36:17.682ZS-EPMC111434753865323710.1016/j.cell.2024.03.027