Mariko Takahashi, Harrison B. Chong, Siwen Zhang, Matthew Lazarov, Stefan Harry, Michelle Maynard, Ryan White, Brendan Hilbert, Magdy Gohar, Maolin Ge, Junbing Zhang, Benedikt Ralf Durr, Gregory Kryukov, Chih-Chiang Tsou, Natasja Brooijmans, Aliyu Alghali, Karla Rubio, Antonio Vilanueva, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, Jonathan Assaad, Farah Makram, Inbal Rachimin, Neha Khandelwal, Pei-Chieh Tien, George Popoola, Nicholas Chen, Kira Vordermark, Marianne Richter, Himani Patel, Tzu-yi Yang, Hanna Griesshaber, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lily Bussema, Lei Shi, Martin Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, David E Fisher, Shyamala Maheswaran, Daniel Haber, Genevieve Boland, Moshe Sade-Feldman, Russ Jenkins, Aaron Hata, Nabeel Bardeesy, Mario Suva, Brent Martin, Brian Liau, Chris Ott, Miguel Rivera, Michael Lawrence, Liron Bar-Peled
bioRxiv 2023.10.20.563287;
doi: https://doi.org/10.1101/2023.10.20.563287
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 NFkB1 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.
