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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.
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.
One bottleneck page and 24 idea pages on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
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