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. Overall design: 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).