{"entity":{"id":"idea-bio1-tumour-restricted-e3-atlas","kind":"idea","name":"Find E3 ligases that only tumours have, and build degraders around them","aka":[],"tldr":"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.","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":["protac-degrader","proteomics"],"targets":[],"drugs":[],"companies":["nurix","kymera"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-toxicity-qol"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":6},"route":"/ideas/idea-bio1-tumour-restricted-e3-atlas/","neighbours":{"technology":[{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"},{"id":"proteomics","kind":"technology","name":"Proteomics & phosphoproteomics","route":"/technologies/proteomics/"}],"company":[{"id":"kymera","kind":"company","name":"Kymera Therapeutics","route":"/companies/kymera/"},{"id":"nurix","kind":"company","name":"Nurix Therapeutics","route":"/companies/nurix/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"}]}}