Cellular tumor antigen p53 (p53) (TP53)

The mutant p53 DNA-binding domain is a primary focus in oncology because the TP53 gene is the most frequently altered gene in human malignancies [1][2]. Most oncogenic mutations are missense substitutions located within this central domain, which normally facilitates sequence-specific DNA binding to regulate genes involved in cell cycle arrest, DNA repair, and apoptosis [1][3]. These mutations typically result in a loss of tumor-suppressive function and often lead to the stabilization and accumulation of the mutant protein, which can exert dominant-negative effects or acquire novel oncogenic gain-of-function properties [2]. Therapeutic strategies targeting this domain aim to restore the wild-type conformation and functional activity using small-molecule chaperones or covalent modifiers [3]. For instance, compounds like Pyrazertinib (PC14586) target the specific Y220C mutation pocket, while Eprenetapopt (APR-246) reacts with cysteine residues to promote refolding [2][4]. Despite the challenges posed by the structural heterogeneity of p53 mutations, targeting this domain remains a high-priority strategy for developing broad-spectrum precision medicines in cancer [3]. Sources: [1] UniProt (P04637); [2] Bykov et al. (2018) Nat Rev Cancer; [3] Duffy et al. (2022) Cancer Treat Rev; [4] ClinicalTrials.gov (NCT04585754).

Other names

Tumor protein p53p53mutant p53mutp53Phosphoprotein p53Antigen NY-CO-13Mutant p53 DNA-binding domain

Restoration of wild-type conformation and transcriptional activity through small-molecule binding or covalent modification of the mutant DNA-binding domain.