Discovery of Novel Naphthylphenylketone and Naphthylphenylamine Derivatives as Cell Division Cycle 25B (CDC25B) Phosphatase Inhibitors: Design, Synthesis, Inhibition Mechanism and in Vitro Efficacy against Melanoma Cell Lines.

Discovery of Novel Naphthylphenylketone and Naphthylphenylamine Derivatives as Cell Division Cycle 25B (CDC25B) Phosphatase Inhibitors: Design, Synthesis, Inhibition Mechanism and in Vitro Efficacy against Melanoma Cell Lines.

Publication date: Jul 11, 2019

CDC25 phosphatases play a critical role in the regulation of the cell cycle and thus represent attractive cancer therapeutic targets. We previously discovered the 4-(2-carboxybenzoyl)phthalic acid (NSC28620) as a new CDC25 inhibitor endowed with promising anticancer activity in breast, prostate and leukemia cells. Herein, we report a structure-based optimization of NSC28620, leading to the identification of a series of novel naphthylphenylketone (NPK) and naphthylphenylamine (NPA) derivatives as CDC25B inhibitors. Compounds 7j, 7i, 6e, 7f and 3 showed higher inhibitory activity than the initial lead, with Ki values in the low micromolar range. Kinetic analysis, intrinsic fluorescence studies and induced fit docking simulations provided a mechanistic understanding of the activity of these derivatives. All compounds were tested in the highly aggressive human melanoma cell lines A2058 and A375. Compound 4a potently inhibited cell proliferation and colony formation, causing an increase of the G2/M phase and a reduction of G0/G1 phase of the cell cycle in both cell lines.

Cerchia, C., Nasso, R., Mori, M., Villa, S., Gelain, A., Capasso, A., Aliotta, F., Simonetti, M., Rullo, R., Masullo, M., De Vendittis, E., Ruocco, and Lavecchia, A. Discovery of Novel Naphthylphenylketone and Naphthylphenylamine Derivatives as Cell Division Cycle 25B (CDC25B) Phosphatase Inhibitors: Design, Synthesis, Inhibition Mechanism and in Vitro Efficacy against Melanoma Cell Lines. 23348. 2019 J Med Chem.

Concepts Keywords
Acid Highly aggressive melanoma
Breast Enzymes
CDC25 Cell cycle
Colony Cdc25
Fluorescence CDC25B
G0 G2 phase
G1 Phase
Induced Fit
Inhibitor
Leukemia
M Phase
Melanoma
Micromolar
Optimization
Phosphatase
Phosphatases
Prostate

Semantics

Type Source Name
pathway BSID G1 Phase
pathway BSID M Phase
gene UNIPROT TAC1
disease DOID leukemia
disease MESH leukemia
drug DRUGBANK Phthalic Acid
disease DOID cancer
disease MESH cancer
pathway BSID Cell Cycle
pathway BSID Cell cycle
gene UNIPROT RASGRF1
gene UNIPROT CDC25C
pathway BSID Melanoma
disease DOID Melanoma
disease MESH Melanoma
gene UNIPROT CDC25B

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