# Macrocyclic peptides to cover protein surfaces that pills cannot

Source: https://onco.cc/ideas/idea-bio1-macrocycle-ppi-campaign/  
OnCo record `idea-bio1-macrocycle-ppi-campaign` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Undruggable cancer proteins such as beta-catenin, MYC and KRAS act through broad flat protein-protein interfaces that small pills cannot cover. Ring-shaped macrocyclic peptides can, some series are cell-permeable, and mRNA display can screen trillions of candidates; the proposal is a focused campaign with open publication of permeability rules.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed test: Run parallel display selections, measure cellular target engagement by NanoBRET, and publish a permeability dataset that others can model.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- companies: [Circle Pharma](https://onco.cc/companies/circle-pharma/), [Generate:Biomedicines](https://onco.cc/companies/generate-biomedicines/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)

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