2. Academic Validation
  3. DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

  • bioRxiv. 2023 Oct 23:2023.10.20.563287. doi: 10.1101/2023.10.20.563287.
Mariko Takahashi,  Harrison B Chong,  Siwen Zhang,  Matthew J Lazarov,  Stefan Harry,  Michelle Maynard,  Ryan White,  Heather E Murrey,  Brendan Hilbert,  Jason R Neil,  Magdy Gohar,  Maolin Ge,  Junbing Zhang,  Benedikt R Durr,  Gregory Kryukov,  Chih-Chiang Tsou,  Natasja Brooijmans,  Aliyu Sidi Omar Alghali,  Karla Rubio,  Antonio Vilanueva,  Drew Harrison,  Ann-Sophie Koglin,  Samuel Ojeda,  Barbara Karakyriakou,  Alexander Healy,  Jonathan Assaad,  Farah Makram,  Inbal Rachman,  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,  Rui Dong,  Lei Shi,  Martin Q 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 A Haber,  Genevieve Boland,  Moshe Sade-Feldman,  Russel Jenkins,  Aaron Hata,  Nabeel Bardeesy,  Mario L Suva,  Brent Martin,  Brian Liau,  Christopher Ott,  Miguel N Rivera,  Michael S Lawrence,  Liron Bar-Peled
PMID: 37961514 DOI: 10.1101/2023.10.20.563287
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.

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