# Find E3 ligases that only tumours have, and build degraders around them

Source: https://onco.cc/ideas/idea-bio1-tumour-restricted-e3-atlas/  
OnCo record `idea-bio1-tumour-restricted-e3-atlas` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Protein-destroying drugs work by hijacking cellular waste-disposal machines. Using a machine that is mostly present in cancer cells would make these drugs safer.

## Summary

Almost all clinical degraders use cereblon or VHL, both broadly expressed, which limits therapeutic index. Human cells have roughly 600 E3 ligases, many with restricted expression; some are highly enriched in tumour or lineage-specific tissue. The proposal is to map ligase expression across normal and tumour tissue atlases, prioritise tumour-enriched ligases, and develop handles for them, thereby making degraders tissue-selective.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: At least five E3 ligases show tumour-to-normal expression ratios large enough that a degrader built on them achieves target degradation in tumour tissue with less than a fifth of the degradation in critical normal tissue.
- Rationale: Selectivity is the main constraint on degrading essential proteins. Cell-type-restricted ligases such as those in liver, prostate and haematopoietic lineage offer a natural targeting mechanism, analogous to how tissue-restricted antigens enable ADCs.
- Proposed test: Bioinformatic prioritisation from GTEx and tumour proteomics, then chemical handle discovery for the top three, with a proof-of-concept degrader of a common target compared against a cereblon-based equivalent for normal-tissue sparing.
- 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

- technologies: [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [Proteomics & phosphoproteomics](https://onco.cc/technologies/proteomics/)
- companies: [Kymera Therapeutics](https://onco.cc/companies/kymera/), [Nurix Therapeutics](https://onco.cc/companies/nurix/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)

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