Tazverik (tazemetostat)

P1, N=24, Recruiting, Epizyme, Inc. | Trial primary completion date: Dec 2025 --> Mar 2026

P2, N=0, Withdrawn, Epizyme, Inc. | N=55 --> 0 | Not yet recruiting --> Withdrawn

In summary, both EZH2 inhibitors showed therapeutic potential in comparison to cisplatin based on cellular and molecular readouts. Additionally, EPZ6438 showed a greater efficacy and higher sensitivity towards HPV+ cells, which was further supported by preliminary in vivo results from the chorioallantoic membrane assay.

P1/2, N=16, Active, not recruiting, National Cancer Institute (NCI) | N=58 --> 16 | Trial completion date: Nov 2025 --> Jan 2027

P2, N=33, Suspended, City of Hope Medical Center | Recruiting --> Suspended

Interestingly, we also found that medications such as prasterone, tazemetostat, isoxyl, gemcitabine, ponsegromab, scx-2023, and nicotinamide could potentially be used in combination with the identified miRNAs to target ferroptosis in CRC. To further validate the stability and reliability of the predicted protein-ligand interactions, molecular dynamics (MD) simulations and MM-PBSA analyses were performed on selected top-ranking complexes, which confirmed their stable and favorable binding and supported the robustness of our docking results. These findings suggest that targeting these miRNAs and their associated genes, along with using the identified drugs, could be a promising strategy for CRC treatment, leveraging the potential of ferroptosis-inducing therapies.

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Jan 2027

In comparison, crotonate showed better blocking effect than EZH2 inhibitor tazemetostat in suppressing breast cancer metastasis. The combination of crotonate and anti-PD-L1 (programmed cell death ligand 1) antibody enhances responses of breast cancer cells to immunotherapy. Together, our findings indicate that crotonate is a promising anticancer drug candidate that suppresses breast cancer growth and metastasis by specifically inducing EZH2 degradation.

Despite the clinical success of tazemetostat, classical small-molecule inhibitors face limitations related to incomplete target occupancy, adaptive resistance, and non-catalytic EZH2 functions...Future directions focus on integrating novel ligases, proteome-wide selectivity mapping, and computational modeling to refine degradation efficiency and minimize off-target effects. Collectively, these developments explain a transformative therapeutic horizon where EZH2-targeting PROTACs are dignified to overcome the intrinsic limitations of enzyme inhibition, offering a new era of epigenetic cancer therapy through targeted protein degradation.

PBRM1 maintains chromatin accessibility for hepatocyte differentiation-related genes. Its loss promotes differentiation toward cholangiocytes during injury or tumorigenesis, driving iCCA development.

P1, N=25, Terminated, Epizyme, Inc. | Phase classification: P3 --> P1

Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.