Tazverik (tazemetostat)

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.

P=N/A, N=145, Active, not recruiting, Eisai Co., Ltd. | Recruiting --> Active, not recruiting

Pediatric STS are rare and biologically heterogeneous. Genomic advances have refined risk stratification and uncovered therapeutic targets; further progress relies on international collaboration and trials.

Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscore the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.

P=N/A, N=63, Not yet recruiting, Ipsen

A cancer cell membrane (CCm)-camouflaged nanoplatform (CCm-HSA-Taz) was engineered to encapsulate the EZH2 inhibitor Tazemetostat (Taz), enabling tumor-targeted delivery...Nuclear medicine imaging revealed reduced tumor glucose metabolism and improved immune cell cytotoxicity. Utilizing components approved by the FDA suggests the potential for this strategy to be translated into clinical settings.

Moreover, we observed changes in the EV cargo derived from EZH2 inhibitor-treated spheroids. Our findings highlight the significant role of EVs in creating an immunosuppressive microenvironment, and underscore the urgent need for further investigation into the regulation of neutrophil biology and function in the PM.