Cellular tumor antigen p53 Y220C mutant (p53 Y220C)

The TP53 Y220C mutant is a specific oncogenic variant of the p53 tumor suppressor protein, which is the most frequently mutated gene in human cancers [1, 8]. This mutation involves a tyrosine-to-cysteine substitution at position 220, creating a unique hydrophobic surface pocket in the DNA-binding domain that destabilizes the protein and causes it to unfold at physiological temperatures [10, 12]. The resulting loss of structural integrity prevents p53 from binding to DNA and executing its essential roles in regulating the cell cycle, DNA repair, and apoptosis, thereby driving tumorigenesis in various solid tumors and hematological malignancies [1, 2, 5]. Unlike many other p53 mutations, the Y220C-induced pocket is highly druggable, serving as a target for small-molecule stabilizers like rezatapopt (PC14586) [3, 10]. These compounds bind to the mutant pocket and act as molecular chaperones to restore the protein to a wild-type-like active conformation [3, 11]. This restoration reactivates the p53 signaling pathway, leading to the expression of downstream target genes such as p21 and MDM2, which ultimately inhibits tumor growth and induces cell death [2, 15].

Other names

TP53 Y220Cp.Tyr220Cysp.Y220CTP53 c.659A>GTumor suppressor p53 Y220C mutant

Small molecule stabilization of the mutant protein to restore wild-type conformation and transcriptional activity.