ideasIdea

Macrocyclic peptides to cover protein surfaces that pills cannot

Many cancer proteins work by touching each other over broad flat surfaces. Small pills cannot cover those, but ring-shaped peptides can, and some can still be taken orally.

Protein-protein interfaces are the defining feature of undruggable targets. Macrocycles occupy a chemical space between small molecules and biologics, with demonstrated cell permeability in some series, and mRNA display can screen trillions of candidates in a single tube. A focused campaign against a defined list of oncology interfaces (for example beta-catenin/TCF, MYC/MAX, KRAS/SOS) with open publication of permeability rules would advance both the targets and the modality.

Hypothesis

mRNA display campaigns against three oncology protein interfaces produce cell-permeable macrocycles with sub-100 nM cellular activity in at least one case.

Rationale

Macrocycles have already produced clinical candidates for previously intractable targets outside oncology; the field's bottleneck is permeability design rules, which are learnable from systematic data.

What would test it

Run parallel display selections, measure cellular target engagement by NanoBRET, and publish a permeability dataset that others can model.

Maturity

preclinical evidence

Who has to act

research

Cost to try

Medium ($1M to $50M)

Years to first evidence

Bottlenecks it attacks

The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

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Macrocyclic peptides to cover protein surfaces that pills cannot

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bottlenecks