eprenetapopt (APR-246)

Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies.

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.

Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes.

Current research has revealed that ASXL1 mutations in MDS predict demethylating agents (HMAs) resistance, the combination of HMAs and Venetoclax (VEN) achieved an ORR of 87%. DNMT3A R882 mutations induce decitabine sensitivity via hemi-methylated enhancer trapping, and TET2 mutations enhance HMAs efficacy only in ASXL1 wild-type contexts (ORR 62.1% vs. co-mutated 19%). RUNX1 aberrations reduce chemotherapy responses (18.9% ORR in high-risk MDS) through DNA repair impairment, while BCOR/EZH2 loss drives cytarabine resistance. TP53 multi-hit lesions correlate with poor survival (OS <12 months) but respond to eprenetapopt-azacitidine (ORR 73%), and IDH1/2 inhibitors achieve durable remissions (ivosidenib ORR 83.3%, mOS 35.7 months). In this paper, we systematically illustrate the correlation between key gene mutations and the response to HMAs, chemotherapy and targeted therapies in MDS patients. This article summarizes the current evidence on gene mutations as predictive biomarkers and discusses the direction of individualized therapy.

Furthermore, we will demonstrate the effectiveness of PRIMA-1 at arresting xenograft growth in an animal model and go on to show that the PRIMA-1 analog APR-246 effectively restores wtp53 tumor suppressor activity in TNBC cells. A brief overview of current clinical trials aimed at reactivating p53 to treat certain cancers is provided. Finally, we discuss the possible use of naturally occurring compounds, which are generally non-toxic, to reactivate mutant p53 and control TNBC progression.

Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming...In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.

Specifically, MRD negativity after cycle 12 strongly predicted OS (33.9 vs 20.4 months; P=.005) and EFS (33.9 vs 10.1 months; P=.004) with a trend for RFS (32.6 vs 13.5 months; P=.06). TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies.

Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.

The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy.

Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

Furthermore, upon exposure to the combination of 10 μM Prima-1MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of CCND1. Hence, these results emphasize the attractiveness of the combination of Prima-1MET and Tam as a therapeutic approach for TNBC and ER+ breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1MET is less than the reported clinically achievable plasma level (∼80 μg/ml).

In this study, we investigated the effects of two purported p53 reactivators, HO-3867 and APR-246, on cell proliferation via half-maximal inhibitory concentration (IC50) analyses using CyQUANT DNA measurements, tumor growth in vivo and gene expression by bulk RNA sequencing in gynecologic cancer cell lines that harbor oncogenic mutations in p53. RNA sequencing data suggest that HO-3867 is acting through both p53-independent and p53-dependent pathways resulting in inhibition of DNA repair pathways including homologous recombination in p53 mutant cancer cells. Significance: The development of resistance to PARP inhibitors is a major problem and a cause of treatment failures in advanced gynecologic cancers, and we show that adding a p53 reactivator such as HO-3867 enhances the efficacy of PARP inhibitors in p53-mutant cancer models.