Tazverik (tazemetostat)

P2, N=42, Active, not recruiting, Hutchmed | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Nov 2024

Treatment with the EZH2 inhibitor tazemetostat restored expression of genes involved in cysteine-methionine metabolism and lipid homeostasis, while suppressing angiogenesis and oxidative stress-related genes...Functionally, EZH2 inhibition dose-dependently reduced cell viability and increased lipid peroxidation in HCC cells. Our findings reveal a novel epigenetic mechanism controlling lipid peroxidation and ferroptosis susceptibility in HCC, providing a rationale for exploring EZH2-targeted therapies in this malignancy.

P2, N=55, Not yet recruiting, Epizyme, Inc. | Trial completion date: Sep 2027 --> Apr 2029 | Trial primary completion date: Sep 2027 --> Apr 2029

P1, N=64, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Potential maintenance regimens may include low-dose traditional chemotherapy or different epigenetic therapies designed to target the epigenetic imbalance that drives RTs. We here review several potential maintenance regimens that may be useful in RTPS.

Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain-containing HKMTs and their opposing HKDMs...It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.

Extended-interval dosing of tazemetostat transformed a partial response into a complete response. Thus, tazemetostat is effective for the treatment of multiple relapsed FL in the leukemic phase.

P2, N=32, Recruiting, Northwestern University | Not yet recruiting --> Recruiting | Initiation date: Apr 2026 --> Sep 2024

Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC.

In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with tazemetostat exhibited superior antitumor immunity, especially when used in combination with anti-PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.

P1, N=64, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=32, Not yet recruiting, Northwestern University | Trial completion date: Apr 2028 --> Nov 2028 | Initiation date: Apr 2024 --> Apr 2026 | Trial primary completion date: Apr 2026 --> Apr 2027

P1, N=30, Recruiting, University of Alabama at Birmingham | Not yet recruiting --> Recruiting

P1/2, N=66, Not yet recruiting, VA Office of Research and Development | Trial completion date: Jun 2028 --> Oct 2028 | Trial primary completion date: Jun 2026 --> Oct 2026

Finally, since only a few drugs, such as azacitidine and tazemetostat, targeting the DNA epigenome, have been approved by the FDA, the next challenge would be to identify molecules for targeting the RNA epitranscriptome. In this review, we highlighted the RNA epitranscriptome pathways implicated in AS, describing their biological functions and their connections to the disease. The identification of epitranscriptome- sensitive pathways could provide novel opportunities to find predictive, diagnostic, and prognostic biomarkers for precision medicine.

P2, N=33, Not yet recruiting, City of Hope Medical Center

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

P1, N=60, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=40, Recruiting, Prisma Health-Upstate | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2025 --> Jan 2026

P1/2, N=102, Active, not recruiting, Epizyme, Inc. | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024

P1/2, N=30, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).

At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy..

We demonstrate that depletion of EZH2 significantly reduces SKP2 protein levels in several cell types, while treatment with EPZ-6438, an EZH2 enzymatic inhibitor, has no effect on SKP2 protein levels...Moreover, EZH2 depletion but not enzymatic inhibition positively regulates the expression of major epithelial-mesenchymal transition (EMT) regulators, such as ZEB1 and SNAIL1, in transformed cells. Our findings shed light on a novel mechanism by which EZH2 exerts regulatory effects on cell proliferation and differentiation through its methyltransferase-independent function, specifically by modulating SKP2 expression.

P1/2, N=42, Recruiting, Vaishalee Kenkre | Trial primary completion date: May 2024 --> Aug 2024

P3, N=612, Recruiting, Epizyme, Inc. | Trial completion date: Apr 2032 --> Mar 2029 | Trial primary completion date: Sep 2029 --> Mar 2026

P1, N=30, Not yet recruiting, University of Alabama at Birmingham | Initiation date: May 2024 --> Aug 2024

In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds...Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

P2, N=267, Completed, Epizyme, Inc. | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Feb 2024

P1/2, N=102, Active, not recruiting, Epizyme, Inc. | Trial completion date: Mar 2024 --> Jun 2024 | Trial primary completion date: Mar 2024 --> Jun 2024

P1, N=24, Recruiting, Epizyme, Inc. | Trial primary completion date: Oct 2024 --> Jun 2025

P1, N=35, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Phase classification: P1a/1b --> P1

In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability...Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

P3, N=612, Recruiting, Epizyme, Inc. | Trial completion date: Mar 2029 --> Apr 2032 | Trial primary completion date: Mar 2026 --> Sep 2029

In conclusion, our study illustrates how EZH2 epigenetically regulates TFR2 expression through H3K27 me3, thereby suppressing ferroptosis. The combination of the tazemetostat with sorafenib exhibits superior synergistic effects in anticancer therapy and sensitizes the HepG2-SR cells to sorafenib, shedding new light on delaying and ameliorating sorafenib resistance.

Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9 l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.

P1/2, N=66, Not yet recruiting, VA Office of Research and Development | Trial completion date: Apr 2027 --> Jun 2028 | Trial primary completion date: May 2025 --> Jun 2026

P2, N=267, Active, not recruiting, Epizyme, Inc. | Trial primary completion date: Jun 2024 --> Feb 2024

P1/2, N=100, Enrolling by invitation, Epizyme, Inc. | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

Reactivation of major apoptotic gene targets was determined at much higher levels in combinatorial treatment protocols than Tazemetostat alone, known to be involved in the induction of intrinsic and extrinsic apoptosis. Overall, we developed an optimized experimental therapeutic platform aiming to ensure the therapeutic effectiveness of Tazemetostat in malignant melanoma while at the same time minimizing toxicity against neighboring non-tumorigenic keratinocyte cells.

P2, N=55, Not yet recruiting, Epizyme, Inc. | Initiation date: Dec 2023 --> Sep 2024

P1, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025