Dokumentdetails
ID
oai:pubmedcentral.nih.gov:1063...
Thema
ArticleAutor
Takahashi, Mariko Chong, Harrison B. Zhang, Siwen Lazarov, Matthew J. Harry, Stefan Maynard, Michelle White, Ryan Murrey, Heather E. Hilbert, Brendan Neil, Jason R. Gohar, Magdy Ge, Maolin Zhang, Junbing Durr, Benedikt R. Kryukov, Gregory Tsou, Chih-Chiang Brooijmans, Natasja Alghali, Aliyu Sidi Omar Rubio, Karla Vilanueva, Antonio Harrison, Drew Koglin, Ann-Sophie Ojeda, Samuel Karakyriakou, Barbara Healy, Alexander Assaad, Jonathan Makram, Farah Rachman, Inbal Khandelwal, Neha Tien, Pei-Chieh Popoola, George Chen, Nicholas Vordermark, Kira Richter, Marianne Patel, Himani Yang, Tzu-yi Griesshaber, Hanna Hosp, Tobias van den Ouweland, Sanne Hara, Toshiro Bussema, Lily Dong, Rui Shi, Lei Rasmussen, Martin Q. Domingues, Ana Carolina Lawless, Aleigha Fang, Jacy Yoda, Satoshi Nguyen, Linh Phuong Reeves, Sarah Marie Wakefield, Farrah Nicole Acker, Adam Clark, Sarah Elizabeth Dubash, Taronish Fisher, David E. Maheswaran, Shyamala Haber, Daniel A. Boland, Genevieve Sade-Feldman, Moshe Jenkins, Russel Hata, Aaron Bardeesy, Nabeel Suva, Mario L. Martin, Brent Liau, Brian Ott, Christopher Rivera, Miguel N. Lawrence, Michael S. Bar-Peled, LironLangue
enEditor
Cold Spring Harbor Laboratory
Kategorie
biorxiv
Jahr
2023
Auflistungsdatum
15.11.2023
Schlüsselwörter
cysteine cancer covalent ligandabilityZusammenfassung
Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of 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 NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors.
We demonstrate that the NFκB1 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.
Takahashi, Mariko,Chong, Harrison B.,Zhang, Siwen,Lazarov, Matthew J.,Harry, Stefan,Maynard, Michelle,White, Ryan,Murrey, Heather E.,Hilbert, Brendan,Neil, Jason R.,Gohar, Magdy,Ge, Maolin,Zhang, Junbing,Durr, Benedikt R.,Kryukov, Gregory,Tsou, Chih-Chiang,Brooijmans, Natasja,Alghali, Aliyu Sidi Omar,Rubio, Karla,Vilanueva, Antonio,Harrison, Drew,Koglin, Ann-Sophie,Ojeda, Samuel,Karakyriakou, Barbara,Healy, Alexander,Assaad, Jonathan,Makram, Farah,Rachman, Inbal,Khandelwal, Neha,Tien, Pei-Chieh,Popoola, George,Chen, Nicholas,Vordermark, Kira,Richter, Marianne,Patel, Himani,Yang, Tzu-yi,Griesshaber, Hanna,Hosp, Tobias,van den Ouweland, Sanne,Hara, Toshiro,Bussema, Lily,Dong, Rui,Shi, Lei,Rasmussen, Martin Q.,Domingues, Ana Carolina,Lawless, Aleigha,Fang, Jacy,Yoda, Satoshi,Nguyen, Linh Phuong,Reeves, Sarah Marie,Wakefield, Farrah Nicole,Acker, Adam,Clark, Sarah Elizabeth,Dubash, Taronish,Fisher, David E.,Maheswaran, Shyamala,Haber, Daniel A.,Boland, Genevieve,Sade-Feldman, Moshe,Jenkins, Russel,Hata, Aaron,Bardeesy, Nabeel,Suva, Mario L.,Martin, Brent,Liau, Brian,Ott, Christopher,Rivera, Miguel N.,Lawrence, Michael S.,Bar-Peled, Liron, 2023, DrugMap: A quantitative pan-cancer analysis of cysteine ligandability , Cold Spring Harbor Laboratory
