p53 protein abundance is a therapeutic window across TP53 mutant cancers and is targetable with proximity inducing small molecules

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 the first generalizable strategy using a small molecule to selectively kill TP53 mutant cells. This molecule binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53 Y220C mutations. Together, these data demonstrate that the abundance of p53 protein provides a therapeutic window for TP53 missense mutant cancers that can be translated into a cell death signal using proximity-inducing small molecules.