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DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
Takahashi, Mariko; Chong, Harrison B; Zhang, Siwen; Yang, Tzu-Yi; Lazarov, Matthew J; Harry, Stefan; Maynard, Michelle; Hilbert, Brendan; White, Ryan D; Murrey, Heather E; Tsou, Chih-Chiang; Vordermark, Kira; Assaad, Jonathan; Gohar, Magdy; Dürr, Benedikt R; Richter, Marianne; Patel, Himani; Kryukov, Gregory; Brooijmans, Natasja; Alghali, Aliyu Sidi Omar; Rubio, Karla; Villanueva, Antonio; Zhang, Junbing; Ge, Maolin; Makram, Farah; Griesshaber, Hanna; Harrison, Drew; Koglin, Ann-Sophie; Ojeda, Samuel; Karakyriakou, Barbara; Healy, Alexander; Popoola, George; Rachmin, Inbal; Khandelwal, Neha; Neil, Jason R; Tien, Pei-Chieh; Chen, Nicholas; Hosp, Tobias; van den Ouweland, Sanne; Hara, Toshiro; Bussema, Lillian; Dong, Rui; Shi, Lei; Rasmussen, Martin Q; Domingues, Ana Carolina; Lawless, Aleigha; Fang, Jacy; Yoda, Satoshi; Nguyen, Linh Phuong; Reeves, Sarah Marie.
Afiliação
  • Takahashi M; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA. Electronic address: mtaka@umich.edu.
  • Chong HB; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Zhang S; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Yang TY; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Lazarov MJ; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Harry S; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • Maynard M; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Hilbert B; Scorpion Therapeutics, Boston, MA 02110, USA.
  • White RD; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Murrey HE; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Tsou CC; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Vordermark K; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Assaad J; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Gohar M; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Dürr BR; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Richter M; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Patel H; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Kryukov G; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Brooijmans N; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Alghali ASO; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Rubio K; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Villanueva A; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Zhang J; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Ge M; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Makram F; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Griesshaber H; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Harrison D; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Koglin AS; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Ojeda S; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Karakyriakou B; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Healy A; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Popoola G; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Rachmin I; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Khandelwal N; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Neil JR; Scorpion Therapeutics, Boston, MA 02110, USA.
  • Tien PC; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Chen N; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
  • Hosp T; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • van den Ouweland S; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Hara T; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Bussema L; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Dong R; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Shi L; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Rasmussen MQ; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Domingues AC; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Lawless A; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Fang J; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Yoda S; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Nguyen LP; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • Reeves SM; Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Cell ; 187(10): 2536-2556.e30, 2024 May 09.
Article em En | MEDLINE | ID: mdl-38653237
ABSTRACT
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 binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisteína / Neoplasias Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisteína / Neoplasias Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2024 Tipo de documento: Article