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

Abstract

AbstractTP53mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations inTP53result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively killTP53mutant cells. This approach uses the increased abundance of p53 protein inTP53mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate the first generalizable strategy using a small molecule to selectively killTP53mutant cells. This molecule binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboringTP53Y220C mutations. Together, these data demonstrate that the abundance of p53 protein provides a therapeutic window forTP53missense mutant cancers that can be translated into a cell death signal using proximity-inducing small molecules.