{"entity":{"id":"idea-bio1-macrocycle-ppi-campaign","kind":"idea","name":"Macrocyclic peptides to cover protein surfaces that pills cannot","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":["circle-pharma","generate-biomedicines"],"institutions":[],"pathways":["wnt","ras-mapk"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":6},"route":"/ideas/idea-bio1-macrocycle-ppi-campaign/","neighbours":{"company":[{"id":"circle-pharma","kind":"company","name":"Circle Pharma","route":"/companies/circle-pharma/"},{"id":"generate-biomedicines","kind":"company","name":"Generate:Biomedicines","route":"/companies/generate-biomedicines/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"}]}}