{"entity":{"id":"idea-bio1-mutant-p53-degrader","kind":"idea","name":"Degrade the damaged p53 protein rather than trying to repair it","aka":[],"tldr":"Some faulty p53 proteins do not just stop protecting the cell; they actively help the cancer. Removing them entirely may be easier than fixing them.","summary":"Gain-of-function mutant p53 accumulates to high levels because it escapes MDM2-mediated turnover, and it drives invasion and chemoresistance in mouse models. A selective degrader exploiting the mutant's dependence on HSP90 or its distinct conformation could deplete it. Precedent: HSP90 inhibitors destabilise mutant p53 and prolong survival in mutant-p53 mouse models, but are too toxic; a targeted degrader would separate the effect from global chaperone inhibition.","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"],"targets":["tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["p53-cell-cycle"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Selective depletion of gain-of-function mutant p53 reduces metastasis and restores chemotherapy sensitivity in mutant-p53 models without affecting wild-type p53 in normal tissue.","rationale":"Mutant p53 accumulation is a distinguishing feature of tumour cells, which gives a natural therapeutic index; degradation is the modality of choice for proteins whose function is structural rather than enzymatic.","test":"Degrader discovery against R175H and R273H with conformation-selective binders; validate in genetically engineered mutant-p53 mouse models measuring metastasis and chemosensitivity.","maturity":"speculative","actor":"research","cost":"medium","horizonYears":8},"route":"/ideas/idea-bio1-mutant-p53-degrader/","neighbours":{"technology":[{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"}],"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/"}]}}