Cellular tumor antigen p53 (Y220C mutant) (p53 Y220C)

The TP53 Y220C mutant p53 protein is a specific oncogenic variant of the p53 tumor suppressor, which is the most frequently mutated gene in human cancer (NIH, 2022). The Y220C mutation involves a tyrosine-to-cysteine substitution at codon 220, which creates a unique hydrophobic pocket on the surface of the DNA-binding domain, destabilizing the protein and causing it to misfold at physiological temperatures (PMID: 23315175). This structural defect leads to a loss of its normal function as a transcription factor, preventing it from regulating genes involved in cell cycle arrest, DNA repair, and apoptosis (AACR, 2021). Consequently, cells harboring this mutation exhibit uncontrolled proliferation and resistance to cell death, contributing to the progression of various solid tumors, including ovarian, breast, and lung cancers (OncoKB, 2024). Therapeutic strategies focus on small-molecule stabilizers, such as rezatapopt (PC14586), which bind specifically to the mutation-induced cavity to restore the wild-type conformation and reactivate its tumor-suppressive transcriptional program (PMV Pharmaceuticals, 2024).

Other names

Tumor protein p53 Y220CTP53 Y220Cp53 Y220C mutantp.Tyr220Cysp.Y220C

Small-molecule stabilization of the mutation-induced hydrophobic pocket in the DNA-binding domain to restore wild-type conformation and transcriptional activity (PMID: 23315175; AACR, 2021).