EPZ015666

Several small-molecule PRMT inhibitors, including GSK3326595 and EPZ015666, have entered early-phase clinical trials for solid tumors. This review examines the mechanistic basis and therapeutic rationale for targeting PRMTs in breast cancer and discusses combination approaches to overcome resistance. We integrate preclinical and emerging clinical data to highlight the potential antiangiogenic and tumor-suppressive effects of PRMT inhibitors, providing insights for future therapeutic strategies for breast cancer.

Treatment of PDAC cells with the protein arginine methyltransferase inhibitors AMI-5 and EPZ015666, but not with the phosphorylation inhibitor SRPIN340, selectively enhanced the level of sEV miR-1246, a miRNA known to be highly enriched in PDAC sEVs...Interestingly, the binding of SRSF1 to miR-1246 was significantly reduced in PDAC cells overexpressing the mutant SRSF1, which was further confirmed using purified wild-type and the mutant SRSF1 proteins. We demonstrate that arginine demethylation of SRSF1 reduces SRSF1-miRNA binding in PDAC cells and enhances selective sEV miRNA enrichment, providing novel insight into SRSF1-mediated sEV miRNA enrichment in PDAC cells and opening up new avenues of investigation on the biology and function of extracellular vesicles in PDAC.

Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells...We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.

Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.

Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

To address this hypothesis, we treated MM cell lines with two clinical trial inhibitors: GSK3368715 (GSK) and EPZ 015666 (EPZ), suppressing PRMT type I and type II inhibitor, respectively...Of note, we found a similar anti-MM effect when treating bortezomib-resistant MM cells with GSK and EPZ, indicating that PRMT type I and type II inhibitors potentially have a substantial clinical impact on relapsed MM...In summary, our preliminary data suggest that suppression of both PRMT type I and type II might provide a potential effective combination treatment for both newly diagnosed and relapsed MM patients. We're currently investigating the underling mechanisms of how PRMTs regulate MM pathology and validating the in vivo efficacy of combination treatment using patient-derived xenograft.

Therefore, we loaded the small EVs with two chemotherapeutic drugs (Temozolomide and EPZ015666) by direct incubation method and the amount of drug loaded was measured by high-performance liquid chromatography (HPLC). Moreover, the system is highly dependent on the drug structure and therefore RWP-1 small EVs were more efficient than RWP-1 small EVs. RWP-1 derived small EVs represent a promising drug delivery tool that can be further investigated in preclinical studies and its combination with PRMT5 inhibitor can be potentially developed in clinical trials for the treatment of PDAC.

Administration of EPZ015666 in both NSG xenograft and HTLV-1-infected humanized immune system (HIS) mice significantly improved survival outcomes. The cumulative findings of this study demonstrate that the epigenetic regulator PRMT5 is critical for the survival, transformation, and pathogenesis of HTLV-1, illustrating the value of this cellular enzyme as a potential therapeutic target for the treatment of ATL.

In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug... Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field.

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (AsO) or/and all-trans retinoic acid. The combination of EPZ015666 with AsO shows synergistic effects on AsO-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with AsO, might be a promising therapeutic strategy against APL.

More importantly, pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 leads to extraordinary radiosensitization in vitro and in vivo in lung cancer. Altogether, our data indicate that PRMT5 methylates and destabilizes Mxi1 to confer radioresistance, suggesting that PRMT5 may be a promising radiosensitization target in non-small cell lung cancer.