This small-molecular reactivator is for TP53 mutations which is found in 50% of human cancers.
Compound 26 (rezatapopt; PC14586), which had the most favorable plasma exposure, was evaluated for its ability to inhibit the growth of NUGC-3 tumor xenografts in nude mice. Oral administration of daily doses of 25 and 50 mg/kg of compound 26 resulted in 33% and 71% inhibition of tumor growth, respectively. Moreover, a higher dose of 100 mg/kg demonstrated an impressive 80% tumor regression. (5,11) As a comparison, compound 24, with lower PK exposure and less potency than compound 26, achieved 54% tumor growth inhibition at a higher dose of 150 mg/kg in the same xenograft model. With a favorable safety profile confirmed in subsequent toxicological studies, compound 26 was selected for further evaluation in human clinical trials.
In conclusion, the combination of structure-based drug design efforts and the incorporation of fluorine substitution has led to the discovery of rezatapopt, the first investigational selective p53 Y220C reactivator. In Phase 1 clinical trials, rezatapopt demonstrated a favorable safety profile in the efficacious dose range, and single-agent clinical efficacy was achieved in heavily pretreated patients across multiple solid tumor types harboring the TP53 Y220C mutation. (15) The Phase 2 portion of the PYNNACLE trial will serve as a registrational study and is currently enrolling. This study will further assess the efficacy and safety of rezatapopt as a monotherapy in patients with locally advanced or metastatic solid tumors who have a TP53 Y220C mutation and are KRAS WT. Results from the clinical trial will be reported in subsequent publications. (16)
Has anyone heard of Rezatapopt (PC14586) Small-Molecule Reactivator of p53 Y220C Mutant in development? What is it?
A I - ChatGPT said:
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Rezatapopt, also known as PC14586, is an investigational small-molecule therapy designed to target a specific mutation in the p53 tumor suppressor protein, known as Y220C. The p53 protein plays a crucial role in regulating cell growth and preventing tumor development. Mutations in the TP53 gene, which encodes the p53 protein, are common in various cancers and often lead to loss of normal p53 function, contributing to tumor progression.
The Y220C mutation creates a crevice in the p53 protein's structure, destabilizing it and impairing its tumor-suppressing capabilities. Rezatapopt is engineered to bind selectively to this crevice, stabilizing the mutant protein and restoring its normal conformation and function. Preclinical studies have demonstrated that rezatapopt can reactivate p53-dependent transcription, leading to cell cycle arrest and apoptosis in cancer cells harboring the Y220C mutation. In mouse models, oral administration of rezatapopt resulted in significant tumor regression and was well tolerated.
PYNNACLESTUDY.COM
Currently, rezatapopt is being evaluated in clinical trials for patients with advanced solid tumors that possess the TP53 Y220C mutation. The Phase 2 portion of the PYNNACLE trial is a global, multi-center, single-arm study assessing the efficacy of rezatapopt as a monotherapy. The trial aims to enroll 114 patients across various cohorts, including ovarian, lung, breast, and endometrial cancers, at approximately 60 sites worldwide. The primary endpoint is overall response rate, as determined by blinded independent central review.
GLOBENEWSWIRE.COM
The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to rezatapopt for the treatment of patients with locally advanced or metastatic solid tumors harboring the TP53 Y220C mutation, recognizing the potential of this targeted therapy to address a significant unmet medical need.
GLOBENEWSWIRE.COM
In summary, rezatapopt represents a promising therapeutic approach aimed at restoring the function of a specific mutant form of p53, thereby potentially inhibiting tumor growth in patients with cancers driven by the TP53 Y220C mutation.
Rezatapopt (also known as PC14586) is an investigational, first‐in‐class small molecule designed to “reactivate” a specific mutant form of the tumor suppressor protein p53 – the Y220C mutation. This mutation creates a unique pocket in the p53 protein that makes it thermally unstable and unable to effectively bind DNA. Rezatapopt binds to this pocket, stabilizing the protein’s structure and restoring its normal, tumor-suppressing functions.
It is currently in early-phase clinical trials (Phase 1/2), being evaluated in patients with advanced solid tumors that harbor the TP53 Y220C mutation, often in a tumor-agnostic (mutation-specific) approach. This approach could potentially benefit a range of cancers that share this mutation. The development program is being led by PMV Pharmaceuticals, and early clinical data have shown promising efficacy and a favorable safety profile in heavily pretreated patients.
I put your post into DeepSeek and here is what I received back ( I didn't check for accuracy but I believe that in general ChatGPT should give a better answer.):
**Rezatapopt (PC14586): A Targeted Therapy for TP53 Y220C Mutations in Cancer**
**Background:**
The TP53 gene, crucial for suppressing tumors, is mutated in 50% of cancers. The Y220C mutation destabilizes the p53 protein, disabling its tumor-suppressing function. Rezatapopt is the first investigational drug designed to reactivate this specific mutation, restoring p53's anticancer activity.
**Preclinical Success:**
- In mouse studies, oral rezatapopt showed **dose-dependent efficacy**:
- Demonstrated a **favorable safety profile**, supporting clinical trials.
**Clinical Development:**
- **Phase 1 Trials**: Confirmed safety and **single-agent efficacy** in heavily pretreated patients with TP53 Y220C-mutated solid tumors.
- **Phase 2 (PYNNACLE Trial)**:
- **Purpose**: Registrational study to assess efficacy/safety as monotherapy.
- **Target Population**: Patients with **locally advanced/metastatic solid tumors** harboring **TP53 Y220C mutation** and **KRAS wild-type** (KRAS WT).
- **Significance**: May support regulatory approval if successful.
**Why It Matters:**
- **Precision Medicine**: Targets a specific genetic alteration (Y220C), exemplifying personalized cancer treatment.
- **KRAS WT Requirement**: KRAS mutations often drive resistance; excluding these patients may enhance response rates.
- **Unmet Need**: Addresses cancers with limited options, especially in advanced/metastatic settings.
**Next Steps:**
Results from the ongoing Phase 2 trial will determine rezatapopt’s potential as a targeted therapy, offering hope for patients with TP53 Y220C mutations—a group historically difficult to treat. Updates will follow publication of clinical data.
The links didn't work and I reported back to DeepSeek. Here is the reply back:
You’re absolutely right—my apologies for the oversight! The links in the original text were truncated (likely during formatting), but here’s how to find the **full, working links**:
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### **1. Clinical Trial Details (PYNNACLE Trial for Rezatapopt/PC14586):**
Thank you. There are so many new developments now including 67-cu-sar-bisPSMA. A cooper isotope that was just fasttracked for FDA approval. There is also one for non expressing PSMA. We have alot to talk about with MO. But first we need to have another PSMA scan since psa has been slightly rising and now 0.65.
Try to get into a centre of excellence and if necessary ask for a second opinion. You are wright, it is lots of going on and we are not doctors. I personally would try to avoid any PSMA treatment because of the nature of the treatment only wiping out the PSMA avid cancer.
I would still considered chemotherapy when it is a right timing. (I am not a doctor to advise you with that.) If docetaxel is toxic try maybe cabasitaxel.
Their are members who are not between us and a PSMA treatment could wipe out the PSMA positive cancer and then the more aggressive PSMA negative CRPC PC could repopulate the space. You need doctors who know exactly what they are doing.
I didn't fully understand your situation. You could try a new less toxic Astra zeneca parp inhibitors undergoing clinical trials if you have genetic mutations.
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