Drugging the "undruggable" p53: a structure-guided strategy against the Y220C mutation.
- 1Peking University Cancer Hospital and Institute, Peking University International Cancer Institute, State Key Laboratory of Molecular Oncology, Frontiers Science Center for Cancer Integrative Omics, School of Basic Medical Sciences, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Peking University Health Science Center, Beijing, China.
Abstract
Tumor Protein p53 (TP53) is the most frequently altered gene in human cancer, yet mutant p53 has long been considered undruggable. The Y220C mutation is exceptional because it both destabilizes the p53 DNA-binding domain (DBD) and creates a unique surface pocket absent in wild-type protein. Availability of structural information enabled structure-based development of rezatapopt (PC14586), which binds this neo-pocket, stabilizes mutant p53, and restores transcriptional tumor suppressor activity. Early clinical studies in the PYNNACLE trial provide proof-of-concept efficacy and reveal emerging on-target resistance. This success supports a broader paradigm in which oncogenic missense mutations can generate druggable neo-pockets, exemplified by KRAS G12C inhibitors such as sotorasib. While most p53 hotspot mutations lack such features, computational pocket detection and structure-guided design may expand targetability across the mutational landscape. Complementary strategies, including covalent stabilization and targeted degradation, further extend this framework, establishing mutation-encoded structural vulnerabilities as actionable therapeutic opportunities.
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BibTeX
@article{song2026drugging,
title = {{Drugging the "undruggable" p53: a structure-guided strategy against the Y220C mutation.}},
author = {Linwan Song and Hua Wang},
journal = {Medical review (2021)},
year = {2026},
month = sep,
doi = {10.1515/mr-2026-0050},
url = {https://europepmc.org/article/MED/42924280},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Drugging the "undruggable" p53: a structure-guided strategy against the Y220C mutation.
AU - Linwan Song
AU - Hua Wang
PY - 2026
DA - 2026/09/01
JO - Medical review (2021)
DO - 10.1515/mr-2026-0050
UR - https://europepmc.org/article/MED/42924280
AB - Tumor Protein p53 (TP53) is the most frequently altered gene in human cancer, yet mutant p53 has long been considered undruggable. The Y220C mutation is exceptional because it both destabilizes the p53 DNA-binding domain (DBD) and creates a unique surface pocket absent in wild-type protein. Availability of structural information enabled structure-based development of rezatapopt (PC14586), which binds this neo-pocket, stabilizes mutant p53, and restores transcriptional tumor suppressor activity. Early clinical studies in the PYNNACLE trial provide proof-of-concept efficacy and reveal emerging on-target resistance. This success supports a broader paradigm in which oncogenic missense mutations can generate druggable neo-pockets, exemplified by KRAS G12C inhibitors such as sotorasib. While most p53 hotspot mutations lack such features, computational pocket detection and structure-guided design may expand targetability across the mutational landscape. Complementary strategies, including covalent stabilization and targeted degradation, further extend this framework, establishing mutation-encoded structural vulnerabilities as actionable therapeutic opportunities.
SN - 2097-0773
SN - 2749-9642
ER -