Abstract
The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins.
Highlights
The cell division cycle 25 (Cdc25) protein family, firstly identified in yeasts as a mitotic inducer [1], comprises three members (Cdc25A, B, and C) of dual-specificity protein phosphatases [2]. These proteins are involved in the activation of cyclin-dependent kinases 1 and 2 (Cdk1-2), through the dephosphorylation of specific threonine and tyrosine residues located in the ATP-binding loop (Tyr15 and Thr14 )
2021)and platform allows for is a drug discovery web-service able to predict affinityon to biological the antiproidentification of several small molecules able to modulate the activity of a chosen spe liferative activity of input structures, through well-established computational protocols
Based on the results described above, among all the tested molecules compound J3955 was identified as the one with the best inhibition effect on the Cdc25 phosphatase and with the highest antiproliferative activity
Summary
The cell division cycle 25 (Cdc25) protein family, firstly identified in yeasts as a mitotic inducer [1], comprises three members (Cdc25A, B, and C) of dual-specificity protein phosphatases [2]. In mammalian cells, these proteins are involved in the activation of cyclin-dependent kinases 1 and 2 (Cdk1-2), through the dephosphorylation of specific threonine and tyrosine residues located in the ATP-binding loop (Tyr and Thr ). 1–2 (Chk1-2) and MAPKAPK-2 kinases, determining their export outside the nucleus, and consequent cell-cycle arrest [7,8] Considering their role in the activation of cyclin-Cdk complexes and, in cell-cycle progression, Cdc25s have become interesting targets
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