rezatapopt (PC14586)

As the most frequently mutated protein across cancers, the tumor suppressor protein p53 is inactivated by the most extensive array of different mutations. Targeting a frequent p53 mutant with the reactivator rezatapopt, recent findings published in the New England Journal of Medicine mark an encouraging step toward clinical utility.

P1, N=14, Recruiting, PMV Pharmaceuticals, Inc | Not yet recruiting --> Recruiting

Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors with KRAS mutations, and whether the strategy can be applied to more common missense mutations remains unclear, the findings offer proof of concept for p53 reactivation.

The Y220N mutant, despite exhibiting high-nanomolar affinity for rezatapopt and substantial stabilization, did not show noticeable effects in cells at the concentrations tested, as rezatapopt binding resulted in only partial compensation for the mutation-induced loss of stability, for which we provide a structural explanation. Our data suggest that the development of clinical pan-Y220C/N/S reactivators, which could benefit an additional 10,000 patients per year, is challenging but not impossible.

In this phase 1 study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof of concept for p53 reactivation. (Funded by PMV Pharmaceuticals; PYNNACLE ClinicalTrials.gov number, NCT04585750.).

Therapeutic approaches include Mtp53 reactivators (e.g., APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations. Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e.g., R175H vs. nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0.01%), tumor immune microenvironment (TIME) features (e.g., TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers.

P1, N=14, Not yet recruiting, PMV Pharmaceuticals, Inc

Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.

In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

P1/2, N=300, Recruiting, PMV Pharmaceuticals, Inc | N=230 --> 300 | Trial completion date: Jul 2026 --> Dec 2027 | Trial primary completion date: Mar 2026 --> Aug 2026

NCT04585750 (ClinicalTrials.gov).

Rezatapopt is an investigational small molecule p53 reactivator that binds specifically to the Y220C-mutant p53 protein without interacting with wild-type or other mutant p53 proteins...There are several wild type Tp53 regulated pathways that could play a role in reversing the inflammatory response and tumor growth observed in this patient case. This perspective explores the signal transduction pathways involved in this cancer mediated inflammation and the extensive reduction of detectable tumor tissue.