{"entity":{"id":"idea-bio1-p53-mutant-reactivator-expansion","kind":"idea","name":"Extend p53 reactivation beyond the Y220C mutation","aka":[],"tldr":"One faulty version of the p53 guardian protein can now be repaired by a drug that plugs a hole in it. Systematically hunting for similar holes in other faulty versions could help far more patients.","summary":"Rezatapopt (PC14586) binds a crevice created by the TP53 Y220C mutation and restores wild-type folding, with responses reported in early trials. Y220C is only around 1 percent of TP53 mutations. A systematic structural and covalent-fragment campaign across the ten commonest TP53 hotspots (R175H, R248Q, R273H, R282W and others), using cryo-EM, deep mutational scanning and AI structure prediction of mutant conformational ensembles, could find analogous pockets or cysteine-reactive sites.","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":["ai-drug-design"],"targets":["tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["p53-cell-cycle"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-vogelstein-surfing-p53-network-nature-2000","paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"At least two additional TP53 hotspot mutants have a reproducible small-molecule-stabilisable conformation that restores p53 transcriptional activity in cells by more than 50 percent of wild-type.","rationale":"TP53 is mutated in about half of all cancers; a mutation-specific reactivator strategy is now clinically validated in principle, and the chemistry (covalent stabilisers, chaperone-like binders) is transferable.","test":"A three-year structure-first campaign with a public compound and structure release; cell-based p53 reporter and transcriptomic restoration assays as the go/no-go for each hotspot.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":6},"route":"/ideas/idea-bio1-p53-mutant-reactivator-expansion/","neighbours":{"technology":[{"id":"ai-drug-design","kind":"technology","name":"AI-driven drug & target discovery","route":"/technologies/ai-drug-design/"}],"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/"},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}]}}