# Design protein degraders small enough to get into the brain

Source: https://onco.cc/ideas/idea-bio2-brain-penetrant-glue-degraders/  
OnCo record `idea-bio2-brain-penetrant-glue-degraders` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

New drugs that destroy cancer proteins are usually too big to enter the brain. Making much smaller versions could bring this approach to brain tumours.

## Summary

Bifunctional degraders typically exceed the size and polarity limits for passive brain entry, whereas molecular glues such as the thalidomide analogues are small and drug-like, and brain-penetrant glue degraders have been reported in neuroscience programmes. Applying glue chemistry to brain tumour dependencies, including transcription factors and fusion oncoproteins, would open targets that current chemistry cannot reach in the brain.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Molecular glue degraders can be optimised to an unbound brain-to-plasma ratio above 0.3 while retaining degradation potency, enabling degradation of a central nervous system tumour dependency in vivo.
- Rationale: Glue degraders are small enough to obey central nervous system drug-likeness rules, unlike classical bifunctional degraders, and degradation is catalytic so lower brain concentrations may suffice. Neuroscience programmes have already demonstrated brain-penetrant glue chemistry.
- Proposed test: A medicinal chemistry campaign with brain exposure as a primary optimisation parameter against one glioma dependency, reporting the brain-to-plasma ratio and in vivo target degradation in tumour tissue.
- Maturity: preclinical-evidence
- Actor: industry

## Sources

- Bottleneck evidence (The brain: barrier and sanctuary): Stupp et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma (NEJM 2005): https://doi.org/10.1056/NEJMoa043330

## Connected records

- cancers: [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/)
- technologies: [AI-driven drug & target discovery](https://onco.cc/technologies/ai-drug-design/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- companies: [C4 Therapeutics](https://onco.cc/companies/c4-therapeutics/), [Kymera Therapeutics](https://onco.cc/companies/kymera/), [Monte Rosa Therapeutics](https://onco.cc/companies/monte-rosa/), [Nurix Therapeutics](https://onco.cc/companies/nurix/)
- terms: [Blood-brain barrier (BBB)](https://onco.cc/terms/blood-brain-barrier/)
- bottlenecks: [The brain: barrier and sanctuary](https://onco.cc/bottlenecks/b-brain-delivery/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)

---
JSON: https://onco.cc/api/v1/entities/idea-bio2-brain-penetrant-glue-degraders.json