Tumor suppressor protein p53 Y220C mutant (p53-Y220C)

The tumor suppressor protein p53 Y220C mutant is a conformational mutant form of the canonical p53 protein (encoded by the TP53 gene), in which tyrosine at position 220 is substituted by cysteine. This mutation destabilizes the core DNA-binding domain, produces a hydrophobic surface cavity that impairs DNA binding and functionality, and leads to loss of tumor suppressor activities. Y220C is among the most prevalent cancer-associated p53 mutations, especially in specific solid tumors. Unlike many p53 mutants, Y220C creates an accessible, druggable crevice that allows for selective stabilization with small molecules—some of which are in clinical development (e.g., rezatapopt). Restoring wild-type p53 activity through small-molecule stabilization has been shown to induce apoptosis and inhibit tumor growth in preclinical and early clinical studies. The Y220C mutant is therefore considered a well-validated precision oncology target, serving both as a direct therapeutic target and a predictive biomarker for the use of p53 reactivator drugs[2][5][6][7][9].

Other names

p53 Y220C mutantTP53 Y220C mutantY220C p53 mutant

Stabilization of the mutant p53-Y220C core domain by small molecule binding to the mutation-induced surface cavity, resulting in restoration of wild-type protein conformation and DNA-binding activity - Reactivation of tumor suppressor signaling and induction of apoptosis in cancer cells - In some cases, increase of zinc-binding affinity of the core domain and prevention of mutant aggregation