epz-5676 and Leukemia--Myeloid--Acute

epz-5676 has been researched along with Leukemia--Myeloid--Acute* in 6 studies

Reviews

2 review(s) available for epz-5676 and Leukemia--Myeloid--Acute

ArticleYear
[Mechanism of A New DOT1L Inhibitor EPZ-5676 and Its Research Progress -Review].
    Zhongguo shi yan xue ye xue za zhi, 2016, Volume: 24, Issue:6

    Leukemia carring translocation at the 11q23 locus is referred to MLL-rearranged (MLL-r) leukemia, and the occurrence of this genetic lesion is associated with a poor prognosis. The most common translocation chromosomes are chromosomes 4,9 and 10. Recently MLL protein was found to interact with DOT1L (DOT1-like) protein, which can promote leukemogenesis. A new DOT1L inhibitor EPZ-5676 can selectively inhibit proliferation, promote apoptosis and differentiation, which was also found to act synergistically with anti-AML (acute myeloid leukemia) and anti-ALL (acute lymphoblastic leukemia) drugs. EPZ-5676 can also induce sustained regression in a rat xenograft model of MLL-rearranged leukemia. Now the novel drug is in phase I of clinical trail. The results suggest that the EPZ-5676 is promising. In this article, the mechanism of EPZ-5676 and its research progress are reviwed.

    Topics: Animals; Apoptosis; Benzimidazoles; Gene Rearrangement; Histone-Lysine N-Methyltransferase; Humans; Leukemia, Myeloid, Acute; Methyltransferases; Myeloid-Lymphoid Leukemia Protein; Translocation, Genetic

2016
Overview: A New Era of Cancer Genome in Myeloid Malignancies.
    Oncology, 2015, Volume: 89 Suppl 1

    In the Myeloid session of the 30th Nagoya International Cancer Treatment Symposium, three speakers were invited. Prof. Clara Bloomfield emphasized the importance of genetic alterations for the prognostic stratification and treatment of acute myeloid leukemia (AML). Dr. Eytan Stein showed that there are promising anti-leukemia effects of IDH2 inhibitor, AG-221, and DOT1L inhibitor, EPZ-5676, based on early-phase clinical studies. Prof. Seishi Ogawa presented a review of the clonal dynamics of secondary myelodysplastic syndrome (MDS) derived from aplastic anemia (AA). From these presentations, we are confident that molecular analysis-based individualized therapies will be realized within a few years.

    Topics: Aminopyridines; Anemia, Aplastic; Antineoplastic Agents; Benzimidazoles; Clonal Evolution; Genome, Human; Hematopoiesis; Histone-Lysine N-Methyltransferase; Humans; Immunosuppressive Agents; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Methyltransferases; Molecular Targeted Therapy; Mutation; Myelodysplastic Syndromes; Triazines

2015

Other Studies

4 other study(ies) available for epz-5676 and Leukemia--Myeloid--Acute

ArticleYear
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss.
    Scientific reports, 2021, 03-31, Volume: 11, Issue:1

    Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.

    Topics: Animals; Benzimidazoles; Cell Cycle Proteins; Cell Self Renewal; Cells, Cultured; Chromosomal Proteins, Non-Histone; Cohesins; Enzyme Inhibitors; Epigenesis, Genetic; Hematopoietic Stem Cells; Histone-Lysine N-Methyltransferase; Histones; Homeodomain Proteins; Humans; Leukemia, Myeloid, Acute; Mice

2021
The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy.
    Scientific reports, 2019, 11-14, Volume: 9, Issue:1

    Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.

    Topics: A549 Cells; Antineoplastic Agents; Autophagy-Related Proteins; B-Cell Lymphoma 3 Protein; Benzimidazoles; Disease Susceptibility; Enzyme Inhibitors; Gene Expression Regulation, Leukemic; Histone-Lysine N-Methyltransferase; Host-Pathogen Interactions; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Leukemia, Myeloid, Acute; MicroRNAs; Opportunistic Infections; Sendai virus; Signal Transduction; Transcription Factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Virus Replication

2019
Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival.
    Theranostics, 2018, Volume: 8, Issue:16

    Acute myeloid leukemia (AML) with an NPM1 mutation (NPMc+) has a distinct gene expression signature and displays molecular abnormalities similar to mixed lineage leukemia (MLL), including aberrant expression of the

    Topics: Animals; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Gene Expression Profiling; Histone-Lysine N-Methyltransferase; Histones; Homeodomain Proteins; Humans; Leukemia, Myeloid, Acute; Methylation; Methyltransferases; Mice, Transgenic; Myeloid Cells; Nuclear Proteins; Nucleophosmin; Protein Processing, Post-Translational; Proto-Oncogene Proteins

2018
DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells.
    The Journal of pharmacology and experimental therapeutics, 2014, Volume: 350, Issue:3

    EPZ-5676 [(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol], a small-molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin-modifying drugs in cellular assays with three human acute leukemia cell lines: MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4), and SKM-1 (non-MLL-r). Studies were performed to evaluate the antiproliferative effects of EPZ-5676 combinations in a cotreatment model in which the second agent was added simultaneously with EPZ-5676 at the beginning of the assay, or in a pretreatment model in which cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents cytarabine or daunorubicin in MOLM-13 and MV4-11 MLL-r cell lines. EPZ-5676 is selective for MLL-r cell lines as demonstrated by its lack of effect either alone or in combination in the nonrearranged SKM-1 cell line. In MLL-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin-modifying drugs also revealed a consistent combination benefit, including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics, including AML SOC drugs and DNA hypomethylating agents in MLL-r cells.

    Topics: Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Growth Inhibitors; Histone-Lysine N-Methyltransferase; Humans; Leukemia, Myeloid, Acute; Methylation; Methyltransferases

2014
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