2. Academic Validation
  3. Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs

Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs

  • Nat Chem Biol. 2025 Nov 3. doi: 10.1038/s41589-025-02051-7.
Ananthan Sadagopan # 1 2 3,  Maximilian Carson 2,  Eriks J Zamurs 2,  Nicholas Garaffo 1 2 3,  Heng-Jui Chang 1,  Stuart L Schreiber 4 5,  Matthew Meyerson 6 7,  William J Gibson # 8 9 10
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 5 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. [email protected].
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 10 Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 41184486 DOI: 10.1038/s41589-025-02051-7
Abstract

TP53 mutant cancers are associated with approximately half of Cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant Cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 Inhibitor in cells harboring TP53Y220C mutations. The resulting bifunctional molecule promotes formation of a p53Y220C-PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces Apoptosis in TP53Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53's transcriptional activity.

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