gsk3235025 and Leukemia

gsk3235025 has been researched along with Leukemia* in 3 studies

Other Studies

3 other study(ies) available for gsk3235025 and Leukemia

ArticleYear
Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9.
    Oncogene, 2019, Volume: 38, Issue:46

    MLL rearrangements play a crucial role in leukemogenesis and comprise a poor prognosis. Therefore, new treatment strategies are urgently needed. We used the CRISPR/Cas9 system to generate an innovative leukemia model based on 100% pure MLL-AF4 or -AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient cells faithfully mimicking the nature of the disease. Thus, it serves as a fundamental basis for pharmacological studies: inhibition of histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is one specific therapeutic approach currently tested in clinical trials. However, success was limited by restricted response warranting further investigation of drug combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines and in MLL mouse models. Here, we used DOT1L and PRMT5 inhibitors in our human MLL-rearranged model demonstrating dose-dependent reduced proliferation, impairment of cell cycle, increasing differentiation, apoptosis, downregulation of target genes and sensitization to chemotherapy. Strikingly, the combination of both compounds led to synergistic anti-tumoral effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias.

    Topics: Adenosine; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; CRISPR-Cas Systems; Drug Synergism; Gene Editing; Hematopoietic Stem Cells; Histone-Lysine N-Methyltransferase; Humans; Isoquinolines; Leukemia; Models, Biological; Myeloid-Lymphoid Leukemia Protein; Phenylurea Compounds; Protein-Arginine N-Methyltransferases; Pyrimidines

2019
Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors.
    Bioorganic & medicinal chemistry letters, 2018, 12-15, Volume: 28, Issue:23-24

    Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the present study, a series of candidate molecules were designed by combining key pharmacophores of formerly reported PRMT5 inhibitors. The in vitro PRMT5 inhibitory testing of compound 4b14 revealed an IC

    Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Isoquinolines; Leukemia; Lymphoma; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein-Arginine N-Methyltransferases; Structure-Activity Relationship

2018
Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization.
    Journal of medicinal chemistry, 2017, 07-27, Volume: 60, Issue:14

    PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC

    Topics: Acetanilides; Antineoplastic Agents; Benzimidazoles; Cell Line; Cell Line, Tumor; Cell Proliferation; Databases, Chemical; Drug Screening Assays, Antitumor; Humans; Kinetics; Leukemia; Lymphoma; Methylation; Models, Molecular; Molecular Docking Simulation; Protein Binding; Protein-Arginine N-Methyltransferases; snRNP Core Proteins; Structure-Activity Relationship

2017