EPZ005687 / Eisai, Ipsen - LARVOL DELTA

Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study. (PubMed, J Biomol Struct Dyn) - "Although the first antiviral drug, Remdesivir, was initially introduced against COVID‑19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection...In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 M. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-M complex with MM-GBSA binding free energy (ΔG) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma. (PubMed, Oncol Rep) - "Pharmacological inhibition of EZH2 using EPZ005687 attenuated MB cell viability and reduced the expression of B7‑H3...Further, EZH2 silencing induced apoptosis and reduced colony‑forming ability in MB cells, whereas EZH2 inhibition in MYC‑amplified C17.2 neural stem cells induced G2/M phase arrest while downregulating B7‑H3 expression. Collectively, the current study positions EZH2 as a viable target for the future development of MB treatments and that targeting EZH2 in combination with B7‑H3 immunotherapy may be an effective treatment for halting MB progression."

IO biomarker • Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CD276 • EZH2 • MIR29A • MYC

Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent. (PubMed, Cancers (Basel)) - "The action of EZH2 inhibitors in this process is independent of the histone methyltransferase activity of polycomb repressive complex 2. Our study reveals a potential therapeutic approach for treating solid tumors by simultaneously targeting EZH2 and BIRC5."

Journal • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor

EZH2 inhibition targets B7-H3 in Myc amplified medulloblastoma (AACR 2022) - "Furthermore, the C17.2_EZH2OXcells were susceptible to EPZ005687 treatment compared to C17.2 control cells, as demonstrated by MTT and FACS. Collectively, our study highlights the therapeutic benefits of targeting EZH2 in Myc-amplified MB cell survival."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CD276 • EZH2 • MYC

The Effect of Direct and Indirect EZH2 Inhibition in Rhabdomyosarcoma Cell Lines. (PubMed, Cancers (Basel)) - "We assessed the direct inhibition of EZH2 by EPZ005687 and the indirect inhibition by 3-deazaneplanocin (DZNep) and adenosine dialdehyde (AdOx) in the embryonal RD and the alveolar RH30 RMS cell line...The results show that direct and indirect inhibition of EZH2 affect cellular functions differently. The alveolar cell line RH30 is more sensitive to epigenetic intervention than the embryonal cell line RD."

Journal • Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells in vitro. (PubMed, Cancer Biol Ther) - "Screening a panel of methyltransferase inhibitors revealed that three inhibitors; GSK126, UNC1999 and EPZ-5687 are the most potent inhibitors that suppressed EZH2 activity selectively on lysine 27 which resulted in increased apoptosis and inhibition of AKT and ERK protein phosphorylation in THP-1 cells. Taken together, our data provide initial evidence that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML. Also, combining EZH2 inhibitors with selinexor may increase the treatment efficacy in these patients."

Journal • Preclinical • Acute Myelogenous Leukemia • Brain Cancer • Glioblastoma • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Inhibition of Polycomb Repressive Complex 2 EZH2 lysine methyltransferase improves tumoricidal activity of macrophages towards mesothelioma cells (AACR 2018) - "...We investigated the effect of a selective EZH2 inhibitor (EPZ005687) on tumoricidal activity of primary human monocyte-derived macrophages. Our data show that inhibition of EZH2 reduces CD206 expression and phagocytic activity of macrophages conditioned in MM pleural effusions (PE-macrophages). Induction of cytotoxic activity of PE-macrophages via PRC2 EZH2 lysine methyltransferase could be of therapeutic value in MM."

Mesothelioma

DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2 (IASLC-WCLC 2015) - Presentation time: 09/08/2015, 10:45 AM - 12:15 PM; Abstract #ORAL25.07; "The chromatin modifier EZH2 was expressed >12-fold higher in SCLC than in normal lung. In addition to the high expression observed in SCLC compared to normal lung...[authors] observed a significant correlation between median EZH2 gene expression and promoter methylation using data from The Cancer Genome Atlas (TCGA)....EPZ-5687 was well-tolerated and demonstrated remarkable efficacy at 100 mg/kg either QD or BID."

Biomarker • Oncology • Small Cell Lung Cancer

Inhibition of Ezh2 in vitro and the decline of Ezh2 in developing midbrain promotes dopaminergic neurons differentiation through modifying H3K27me3. (PubMed, Stem Cells Dev) - "Treated with Ezh2-selective inhibitor EPZ005687 repressed the trimethylation of H3K27 and enhanced differentiation of DA neurons in VM-NSCs cultures...Deletion of Ezh2 by RNA interference approach promoted DA neurons differentiation during midbrain development. Overexpression of Ezh2 enhanced cell self-renewal and did not affect DA neurons differentiation."

Journal • Preclinical

Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57 and TP53INP1 in mantle cell lymphoma. (PubMed, Cancer Biol Med) - "We also evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycle distribution and apoptosis in vitro...Our study suggests that EZH2 participates in the pathogenesis of MCL which may serve as a potential biomarker for prognosis prediction. The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL."

Biomarker • Journal