Emerging EZH2 Inhibitors and Their Application in Lymphoma

  title={Emerging EZH2 Inhibitors and Their Application in Lymphoma},
  author={Jennifer K. Lue and Jennifer E. Amengual},
  journal={Current Hematologic Malignancy Reports},
  • J. LueJ. Amengual
  • Published 15 August 2018
  • Biology, Medicine
  • Current Hematologic Malignancy Reports
Purpose of ReviewEnhancer of Zeste Homolog 2 (EZH2) is histone methyltransferase and catalyzes the methylation of histone 3 lysine 27, a mark of transcriptional repression. Various studies have elucidated the complex role of EZH2 in both normal biology and tumorigenesis. Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.Recent FindingsActivating mutations and overexpression of EZH2 are… 

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27.

EZH2-Targeted Therapies in Cancer: Hype or a Reality

This review highlights the recent advances in targeting EZH2, its successes, and potential limitations, and discusses the future directions of this therapeutic subclass.

Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure-Activity Relationships Insights and Evolution Prospects.

This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZh2 degradation agents with a focus on their design strategies, structure-activity relationships (SARs), and safety and clinical manifestations.

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.

Compound 20 exhibited excellent inhibitory activity against HDAC1 and EZH2 and showed good antiproliferation activity against MV4-11, which suggested that 20 may be a promising drug candidate for treating hematological malignancies.

Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation

The existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex is summarized and the potential application of existing EZh2 inhibitors in cancer patients harboring mutations in SWI-SNF proteins is discussed.

Hypomethylating Agents in Lymphoma

Investigation of DNMT inhibitors as a means of improving responsiveness to chemotherapy in DLBCL patients, or as monotherapy or in combination with other epigenetic agents in the treatment of TCL, concludes that new treatment options that target the pathogenesis of disease are needed.

BET and EZH2 Inhibitors: Novel Approaches for Targeting Cancer

Two new classes of epigenome-targeting agents are reviewed: the bromodomain and extraterminal domain proteins (BET) inhibitors and the enhancer of zeste homolog (EZH2) inhibitors.

Deregulation of Polycomb Repressive Complex-2 in Mantle Cell Lymphoma Confers Growth Advantage by Epigenetic Suppression of cdkn2b

Results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH 2 inhibitors may have therapeutic potential in the patients with MCL.

Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.

The discovery of potent and orally bioavailable EED ligands with good solubilities is disclosed, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.

A chemical strategy toward novel brain-penetrant EZH2 inhibitors

This work has identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity and reports the first brain-penetrant EZh2 inhibitor, TDI-6118 (compound 5).



EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.

Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation

  • W. QiH. Chan E. Li
  • Biology
    Proceedings of the National Academy of Sciences
  • 2012
A potent and selective small molecule inhibitor, EI1, is developed, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine, providing strong validation of EzH2 as a potential therapeutic target for the treatment of cancer.

Epigenetic Targeting with EZH2 and HDAC Inhibitors Is Synergistic in EZH2 Deregulated Lymphomas

The potential synergy of EZH2 and HDAC inhibitors co-treatment and the impact of the combination on the function of the PRC2 complex was assessed via co-immunoprecipation in these cell lines.

EZH2 Inhibitor EPZ-6438 Synergizes With Anti-Lymphoma Therapies In Preclinical Models

It is shown that glucocorticoid receptor agonism may be a key mechanism of the combination benefit observed with CHOP, as the antiproliferative effect of EPZ-6438 was enhanced by either prednisolone or dexamethasone alone, in several EZH2 mutant lymphoma cell lines (in vitro).

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia.

This study provides the detailed profiling for a set of chemicals to manipulate EZh2 and EZH1 and establishes specific enzymatic inhibition of polycomb repressive complex 2 (PRC2)-EZH2 and PRC2-EzH1 by small-molecule compounds as a novel therapeutics for MLL-rearranged leukemia.

Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma

Activity of EPZ-6438 is characterized in preclinical models of NHL to confirm the dependency of EZH2-mutant NHL on EzH2 activity and portend the utility ofEPZ- 6438 as a potential treatment for these genetically defined cancers.

A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells.

The discovery of EPZ005687 is reported, a potent inhibitor of EZH2 that reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells.

EZH2: Not EZHY (Easy) to Deal

A better understanding of the complex epigenetic regulatory network controlling EZH2 expression and target genes facilitates the design of novel therapeutic interventions, and highlights the multifaceted role of EH2, as either a transcriptional activator or repressor depending on the cellular context.

First-in-Human Study of the EZH1/2 Dual Inhibitor DS-3201b in Patients with Relapsed or Refractory Non-Hodgkin Lymphomas — Preliminary Results

This Phase I study explored safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of DS-3201b in patients with relapsed or refractory non-Hodgkin lymphomas (NHLs), including adult T-cell leukemia-lymphoma (ATL) associated with human T-LYmphotropic virus type I.