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DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Mariko Takahashi1, Harrison B Chong1, Siwen Zhang1
1Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Abstract:
Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for 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 NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 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.
Insights
Cysteine targeting varies across cancers due to cellular differences. Researchers developed DrugMap to identify and target specific cysteines in transcription factors NF-κB1 and SOX10, disrupting cancer signaling.
Area of Science:
- Chemical biology
- Cancer research
- Proteomics
Background:
- Covalent inhibitors targeting cysteine residues have advanced cancer therapy.
- Understanding how oncogenic contexts affect cysteine targeting is crucial but unknown.
Purpose of the Study:
- To investigate the variability of cysteine ligandability across diverse cancer cell lines.
- To identify cell-intrinsic features influencing cysteine targeting.
- To develop covalent probes for targeting oncogenic transcription factors.
Main Methods:
- Development of "DrugMap," a comprehensive atlas of cysteine ligandability across 416 cancer cell lines.
- Analysis of cellular redox states, protein conformations, and genetic mutations.
- Design and synthesis of covalent ligands for identified actionable cysteines.
Main Results:
- Cysteine ligandability significantly varies across cancer cell lines.
- Differences are attributed to cellular redox state, protein conformation, and genetic mutations.
- Actionable cysteines in NF-κB1 and SOX10 were identified, and specific covalent ligands were developed.
- NF-κB1 probe blocked DNA binding; SOX10 ligand disrupted melanoma signaling by altering protein interactions.
Conclusions:
- Cysteine ligandability exhibits heterogeneity across cancer types.
- Cell-intrinsic factors dictate cysteine targeting efficacy.
- Covalent probes can effectively disrupt oncogenic transcription factor activity, offering therapeutic potential.
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