Novel agent restores p53 function in p53-mutated AML
MD Anderson Research Highlight July 11, 2025
Mutations of the TP53 gene are very common in leukemias and other cancers. They are predictors of poor response to therapies and are also associated with poor survival. To address this, , ., and colleagues investigated the first agent specifically targeting a p53 mutant protein made by a unique TP53 mutation called Y220C in leukemias. The agent, rezatapopt, partially restores the normal function of the mutant p53 protein. Researchers discovered that two other proteins block the antitumor power of rezatapopt and, further, that the reactivated p53 does not bind to pro-survival BCL-2 proteins as normal p53 does. Combinations of rezatapopt along with inhibitors of these other proteins induced strong cancer cell death and improved survival in vivo. A clinical trial is underway to examine this strategy in patients, offering the first tailored approach to fighting a specific TP53 mutation in acute myeloid leukemia (AML). Learn more in .
While rezatapopt can partly fix the mutant Y220C-p53 protein, it has limited ability to kill leukemia cells. Combining it with venetoclax or MDM2/XPO1 inhibitors enhances its anti-leukemia activity.