"DrugMap" Expected to Accelerate Cancer Drug Discovery
Key findings
- Relying on advances in cysteine-focused chemical proteomic analyses, researchers at Mass General Cancer Center developed "DrugMap," a comprehensive dataset of cysteine ligandability across 25 types of cancer
- For a subset of cysteines the team discovered heterogeneity in targeting, which was explained in part by the metabolic state of cancer cells and by genetic mutations near the cysteine within proteins
- These insights were used to develop chemical probes that manipulate the activity of NFκB1 and SOX10, two oncogenic transcription factors previously considered undruggable
- The development of DrugMap and the two chemical probes provide a roadmap for oncology-focused ligand discovery and drug development
Approximately 400 cancer drivers have been discovered, but fewer than 10% are targeted by the newer precision therapies. Furthermore, that subset is almost entirely composed of protein kinases or enzymes. There's a critical need to extend drug targeting to other classes of oncogenic drivers.
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Many precision anti-cancer drugs target cysteine, an amino acid in proteins that has special reactivity. In an exciting advance, Liron Bar-Peled, PhD, and Michael Lawrence, PhD, principal investigators in the Krantz Family Center for Cancer Research at Mass General Cancer Center, and colleagues have developed DrugMap, a quantitative atlas of cysteine ligandability—that is, protein druggability—across numerous cancer types.
As reported in Cell and now available online, DrugMap is expected to guide the development of new chemical probes/tool compounds and, eventually, new drugs.
Methods
The researchers undertook systematic cysteine ligandability mapping of 416 cancer cell lines across 25 cancer types, each represented on average by about 18 cell lines (rarer cancers were represented by at least two cell lines). They also built a unique computational pipeline for cysteine set enrichment analysis, which showed what types of proteins are druggable and the structural features that make a protein druggable.
Heterogeneity in Cysteine Ligandability
There's wide variability in patient response to targeted cysteine-reactive cancer therapies, which has been attributed to inter- and intra-tumoral heterogeneity. Unexpectedly, the team discovered that for some cysteines, ligandability itself is heterogeneous. It was influenced in part by variation in levels of reactive oxygen species in cancer cells and by cysteine-proximal mutations in proteins.
Changes in cysteine ligandability were associated with ligand- and mutation-induced changes in protein structure—and therefore protein function. Deciphering how specific cell states and protein structures affect cysteine ligandability will be important for designing new drugs and predicting which tumors might respond to specific drugging approaches.
Chemical Probes
Leveraging findings from DrugMap, the team developed covalent ligands (chemical probes) that manipulate the activity of two oncogenic transcription factors many experts have considered undruggable:
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Nuclear factor κB1 (NF-κB1)—the ligand functioned by disrupting DNA interactions
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SRY-box transcription factor 10 (SOX10)—the ligand acted as "molecular glue," disrupting transcription and ultimately blocking proliferation of melanoma cells
A Roadmap for Drug Development
DrugMap is expected to provide a basis for investigations to better understand cysteine liganding, identify potential new therapeutic targets, and explain why certain anti-cancer drugs work well and others don't.
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