Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 in vivo by Rezatapopt (PC14586), a Small Molecule Reactivator [in vivo]

Restoration of the tumor suppressor function of tumor-associated p53 mutants, including tumors harboring the TP53 Y220C mutation, has posed a significant challenge and remains an attractive target for therapeutic discovery. Here, we describe a clinical candidate Rezatapopt (PC14586) designed to stabilize the p53 Y220C mutant protein and restore wild-type (WT) p53 function. Extensive transcriptomics analysis of NUGC-3 xenografted tumors harboring the TP53 Y220C mutation following PC14586 treatment revealed the induction of p53 direct target genes, including protein-coding genes and long non-coding RNAs (lncRNAs), and repression of cell cycle progression-associated genes in a distinct temporal pattern. Our data demonstrate that PC14586 administration inhibited tumor growth in vivo via the induction of WT p53 transcriptional signatures, including a sustained transcriptional repression of genes involved in cell cycle regulation. Following these investigations, rezatapopt (PC14586) was identified as a clinical candidate and is currently being evaluated in the registrational Phase 2 PYNNACLE study. To investigate the selectivity and robustness of PC14586 in reactivating the p53 Y220C mutant protein to p53 WT function in tumors, we treated xenografted human tumors carrying TP53 Y220C mutation (NUGC-3) in nude mice with PC14586 (100 mg/kg) and vehicle controls in 4 biological repeats for each. We performed comparative gene expression profiling analysis of RNA-seq data from NUGC-3 xenografted tumors with PC14586 treatments at different time points (n=4 each) versus consolidated vehicle treatments (n=12).