Extend p53 reactivation beyond the Y220C mutation
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.
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
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not linked directly; found by shared links- IdeaDegrade the damaged p53 protein rather than trying to repair it
Shares p53 / RB / cell-cycle checkpoint, TP53, The undruggable drivers.
- CompanyBulsara Bioworks
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- IdeaMilestone prizes for first-in-class mechanisms reaching human proof of concept
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