DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Author:
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.ORCID, 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
Abstract
AbstractCysteine-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 developedDrugMap, 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.
Publisher
Cold Spring Harbor Laboratory
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