ideasIdea
Find E3 ligases that only tumours have, and build degraders around them
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.
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.
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.
What would test it
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
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- Toxicity and quality of life are undervalued · Trials measure how long people live, not how they live. Side-effects are under-reported and under-treated.