TP53 Y220C

Furthermore, AG3 induced p53-dependent cytotoxicity and enhanced chemotherapy response. This study presents a novel compound with p53-Y220C reactivation potential, highlighting its promise for further development.

Although the arylated cysteines are both near the DNA-binding interface, fluorescence polarization experiments using five different response elements confirm that DNA binding appears not to be compromised. The compounds present an interesting starting point for both general and mutant specific p53 stabilization.

Negative control compounds that are unable to form a ternary complex lack these activities, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in cancer.

We demonstrate that this reactivation induces the transcription of canonical p53 target genes and elicits antiproliferative effects in cancer cell lines. A combination of this DARPin with an mRNA/lipid nanoparticle-based transfection approach may have the potential to reactivate most TS p53 mutants and resensitize cancer cells to chemotherapy.

Given the rarity of the tumor, it is crucial to distinguish it from morphological mimics to inform appropriate patient management. Treatment approaches are typically based on protocols for primary breast cancer, given the histological and biological similarities between these tumors and breast tissue.

These results demonstrate that LLQ-45 activates the antitumor function of p53 Y220C via covalent modification, thereby suppressing tumor cell growth. This study provides a framework for targeting neomorphic pockets and advances targeted cancer therapies.

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.).

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