DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

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.