cgp-57380 and Leukemia--Myeloid--Acute

Phosphorylation of the eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is essential for oncogenesis but unnecessary for normal development. Thus, pharmacological inhibition of Mnks may offer an effective and non-toxic anti-cancer therapeutic strategy. Herein, we report the discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors. Docking study of 7a in Mnk2 suggests that the compound is stabilised in the ATP binding site through multiple hydrogen bonds and hydrophobic interaction. Cellular mechanistic studies on MV-4-11 cells with leads 7a, 8e and 8f reveal that they are able to down-regulate the phosphorylated eIF4E, Mcl-1 and cyclin D1, and induce apoptosis.

Topics: Adenosine Triphosphate; Apoptosis; Carboxylic Acids; Cell Cycle; Cell Proliferation; Drug Discovery; Eukaryotic Initiation Factor-4E; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines; Structure-Activity Relationship; Thiophenes; Tumor Cells, Cultured

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; MCF-7 Cells; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Purines; Pyrimidines; Structure-Activity Relationship; Thiazoles