作者
Mariko Takahashi,Harrison B. Chong,Siwen Zhang,Mirella Lazarov,Stefan Harry,Michelle Maynard,Ryan R. White,Brendan Hilbert,Magdy Gohar,Mengyu Ge,Junbing Zhang,Benedikt R Dürr,Gregory V. 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,Jiali Fang,Satoshi Yoda,Linh Phuong Nguyen,Sarah Reeves,Farrah Nicole Wakefield,Adam Acker,Sarah E. Clark,Taronish D. Dubash,David E. Fisher,Shyamala Maheswaran,Daniel A. Haber,Genevieve M. Boland,Moshe Sade-Feldman,Russell W. Jenkins,Aaron N. Hata,Nabeel Bardeesy,Mario L. Suvà,Brent R. Martin,Brian B. Liau,Chris Ott,Miguel N. Rivera,Michael S. Lawrence,Liron Bar-Peled
摘要
Abstract 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.