TP53-mutant cancers are associated with almost half of cancer deaths, but attempts to target the gene therapeutically have invariably failed or been off-target. One common feature of TP53-mutated cancers, especially those with missense mutations, is accumulation of mutant p53 protein in the cell. To target such cells with specificity, Ananthan Sadagopan, Stuart Schreiber, Matthew Meyerson, and Will Gibson developed a bifunctional molecule capable of binding the Y220C mutant of p53 while carrying a cell toxin, causing the toxin to amass just in mutated cells. Their study, published in Nature Chemical Biology, provides a generalizable framework for targeting TP53 missense mutations therapeutically. 🔗: https://lnkd.in/dkdJK9VA #BroadInstitute #Science #ScienceNews #Research #ScientificResearch
A remarkable step forward for targeting TP53 mutations. The ability to leverage mutant p53 accumulation with such precision opens a new therapeutic path that many patients have been waiting for. Grateful to see this level of scientific rigor driving real possibility 🔬
Ron Shprints
1d
Amazing work!!
See about Nonsteroidal Anti-Inflammatory Drugs (NSAIDs and p53 signaling. 😉
The induced proximity concept here is clean: a Y220C-selective p53 ligand is used to concentrate a PLK1 inhibitor, drive a ternary complex, mislocalize PLK1, and trigger a selective G2/M arrest and apoptosis signal in TP53 Y220C cells, while sparing WT TP53. The honest part is the limitation too: today this is allele-specific because Y220C has a unique cavity, so translating to other mutants will live or die on finding equally selective binders. Also worth highlighting that they already see the obvious resistance path, antigen loss via reduced mutant p53 abundance under chronic intermediate dosing. This is the kind of mechanistically anchored work TP53 targeting has needed for a long time.