pinometostat (EPZ-5676)

We highlight the role of SAGs in MRLC. SOD2, ALDH2, MME and IGFBP1 were potential biomarkers and therapeutic targets. EPZ5676 was a potential drug for treating MRLC by targeting these four genes.

In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice...TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.

Substantial previous work has developed catalytic inhibitors like pinometostat, which showed limited clinical efficacy...In vivo studies with DOT1L808 showed its ability to achieve complete tumor regression in an orthotopic leukemia model without overt toxicity. These results establish protein degradation as a promising therapeutic strategy for MLL-rearranged leukemias.

These findings suggest that the anti-breast cancer effect of DOT1L inhibition is mediated by multiple mechanisms, including activation of innate immune signaling.

Therapeutic strategies targeting DOT1L using inhibitors, such as EPZ-5676, have shown promise in preclinical and clinical studies, highlighting their potential as versatile targets for precision oncology. This review summarizes the recent findings on DOT1L's involvement in cancer development and its potential as a therapeutic target.

Furthermore, BBR synergized with the menin-MLL inhibitor VTP50469 and showed additive effects with the DOT1L inhibitor EPZ5676, the latter of which restored BBR sensitivity in previously BBR-unresponsive cells. These findings establish EYA PTP activity as a therapeutic target in MLL-r leukemia, support the use of EYA expression for identifying patients likely to benefit from BBR treatment, and highlight the potential of BBR-based combinations to improve response in this high-risk leukemia subtype.

Menin inhibitors (e.g., Revumenib, Ziftomenib) disrupt the Menin-KMT2A interaction, suppressing HOXA/MEIS1 and promoting differentiation. DOT1L inhibitors (e.g., Pinometostat) show promise in combination therapies, while novel approaches like WDR5 inhibitors and PROTAC-mediated degradation are expanding treatment options. Despite progress, challenges remain, including optimizing minimal residual disease monitoring, overcoming resistance, and validating biomarkers. This review emphasizes the imperative to translate molecular insights into personalized therapeutic regimens, offering renewed hope for patients afflicted by this historically refractory malignancy.

The compounds incorporate an aminopyrimidine moiety coupled to a functionalized aryl based on the structure of published DOT1L inhibitors that have entered clinical trials (EPZ-5676, pinometostat)...We identified compound 19d (IC50 = 8.0 μM) as a DNMT3a inhibitor, and 1n (EC50 = 19.0 μM), 1p (EC50 = 4.8 μM) and 19g (EC50 = 11.0 μM) as PRMT4 inhibitors based on the in silico approach that was employed. The in vitro ADMET profile of the compounds matched with the generally accepted lead-like criteria and encouraged the further optimization of these non-nucleosidic hit compounds.

Indeed, with molecular docking and biochemical experiments, we identified EPZ-5676 as a YTHDC1 inhibitor, and combination of EPZ-5676 with Cytarabine (Ara-c) significantly improved the efficacy of chemotherapy in B-ALL mouse models using YTHDC1high primary and lined B-ALL cells. Collectively, YTHDC1 is required for DDR in B-ALL cells by upregulating DDR-related gene expression via stabilizing m6A-modified KMT2C mRNA, thereby leading to increased histone H3K4 methylation, and targeted inhibition of YTHDC1 is a potentially new therapeutic strategy against B-ALL, especially YTHDC1high B-ALL.

Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.

P1/2, N=6, Terminated, National Cancer Institute (NCI) | Phase classification: P1b/2 --> P1/2

Finally, drugs with high sensitivity to HNSCC (such as 5-Fluorouracil, Temozolomide, Carmustine, and EPZ5676) were explored and analyze the malignant characteristics of HNSCC. Malignant features associated with HNSCC include angiogenesis, EMT, and the cell cycle. This study has opened up new prospects for the prognosis, prediction, and clinical treatment strategy of HNSCC.