Tazverik (tazemetostat)

P2, N=164, Completed, Institut Bergonié | Active, not recruiting --> Completed | Trial completion date: Dec 2027 --> Jul 2025

EZH2 plays a crucial role in promoting malignant phenotypes in EC, and its expression level correlates with cellular sensitivity to EZH2 inhibitors. These findings suggest that EZH2 could serve as a valuable therapeutic target and predictive biomarker for personalized medicine in EC.

In this study, we systematically investigate the correlation between Tazemetostat, a highly selective EZH2 inhibitor, and alterations in the eccDNA landscape and transcriptional programs in ovarian cancer...By integrating multi-omics and spatial single-cell transcriptomics, we uncovered a novel epigenetic-eccDNA axis that may contribute to oncogenic plasticity and therapeutic resistance. This could result in a paradigm shift in targeting eccDNA-driven malignancies.

Conversely, multitarget hybrids such as Olaparib-Tazemetostat (33) and Tazemetostat-resorcinol (170) maintained robust cellular efficacy through synergistic epigenetic and DNA-repair modulation. Future perspectives emphasize rational design strategies integrating dual targeting, computational modeling, and covalent functionalities to enhance therapeutic durability. Collectively, these advances explain the evolving therapeutic horizon of non-PROTAC and dual EZH2 inhibitors, offering an outline for next-generation EZH2 inhibitors.

Comparative ADME and drug-likeness analyses highlight key molecular determinants of potency and pharmacokinetic performance. Finally, an outline is given on emerging opportunities and challenges shaping the future of pyridone-based EZH2 inhibitor rational design and optimization strategies for the development of next-generation anticancer candidates.

On the other hand, NDGA inhibited CBP/p300, decreased H3K27ac levels, and synergized with the EZH2 inhibitor EPZ6438 against PC3 cells. In conclusion, NDGA is a potential epigenetic antineoplastic agent that downregulates EZH2 and H3K27me3 through the NRP1 and PI3K/AKT/mTOR pathways and exerts a synergistic antitumor effect with H3K27ac and EZH2 inhibitors, suggesting that it could be a valuable therapeutic option for prostate cancer.

For perturbation, the EZH2 inhibitor tazemetostat was evaluated in the CRPC-relevant C42 cell line with H3K27me3 readouts and transcriptomic profiling, with key changes validated by RT-qPCR...This multi-layer integrative analysis suggests that EZH2 is associated with proliferative malignant states and immunosuppressive microenvironment features in advanced PCa, including Treg-linked crosstalk. Transcriptomic profiling following EZH2 inhibition supports modulation of these programs by EZH2-targeted perturbation, while functional and causal mechanisms warrant further investigation.

P1, N=24, Recruiting, Thomas Jefferson University | Suspended --> Recruiting | Trial completion date: Jan 2026 --> Jan 2029 | Trial primary completion date: Jan 2026 --> Jan 2028

In mouse xenografts, EPZ-6438 enhanced OS cell sensitivity to doxorubicin, suggesting therapeutic synergy. Targeting NPM1 or its downstream effectors effectively suppresses ALT activity and enhances chemotherapy response. These findings provide new mechanistic insights into telomere regulation in ALT-positive tumors and highlight the therapeutic potential of NPM1-centered pathways in OS.

On the other hand, depletion of DE Tfh cells via Ezh2 gene deletion, inhibition of EZH2 (using FDA-approved drug, tazemetostat), or anti-CXCR6 mAb led to tumor regression. These findings may be relevant to a subset of human AITL cases since we found that ~20-30% of AITL patient samples have concomitantly elevated expression of CXCR6, IL-18R1, and IFNG. Our study identified a pathogenic Tfh-like subset essential for AITL tumor progression in a mouse model and suggests that identifying and targeting a DE Tfh-like subset in AITL patients might be an effective strategy.

P1/2, N=100, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

In this study, EZH2 levels were modulated by CRISPR/Cas9 gene editing and PRC2 activity was inhibited with EZH2 inhibitor EPZ6438 or EED inhibitor MAK683. This was accompanied by increased expression of other PcG genes, including EZH1, CBX2, RING1, EED, and SUZ12, suggesting a compensatory interaction between PRC2 and PRC1 complexes. These findings provide significant clinical relevance, both in elucidating the mechanisms of novel molecular targets and in guiding treatment strategies for lung cancer when using epigenetic inhibitors.