article · Journal of Enzyme Inhibition and Medicinal Chemistry
Three series of hybrid chemical compounds combining oxindole and benzofuran structures were designed, synthesised, and evaluated as dual inhibitors of the enzymes CDK2 and GSK-3beta, which are known therapeutic targets in breast cancer. Among the evaluated structures, the N1-unsubstituted oxindole derivatives demonstrated moderate to strong anti-cancer activity against MCF-7 and T-47D breast cancer cell lines. Three specific compounds, designated 5d, 5e, and 5f, exhibited potent cytotoxic activity comparable to or exceeding that of the reference drug staurosporine. Further testing revealed that compounds 5d and 5f achieved potent dual enzyme inhibition at nanomolar concentrations against both target kinases. In cell assays, the most effective hybrids triggered cell cycle arrest in the G2/M phase and induced apoptosis in MCF-7 cells. Molecular modelling confirmed that these active compounds bind effectively into the key hinge regions of both targeted enzymes.
Targeting multiple cancer-promoting proteins simultaneously is an important strategy to improve therapy outcomes and overcome drug resistance. By designing single molecules that inhibit both CDK2 and GSK-3beta, this research provides new chemical starting points for developing targeted treatments against breast cancer, demonstrating how specific structural modifications directly influence enzyme inhibition and cancer cell destruction.
This work represents early-stage medicinal chemistry and preclinical drug discovery. The identified compounds could serve as lead molecules for pharmaceutical companies and oncology researchers seeking to develop dual-target kinase inhibitors for breast cancer therapies. However, the findings are currently limited to laboratory synthesis, computational modelling, and in vitro cellular assays, meaning that extensive preclinical validation, toxicity profiling, and in vivo testing are required before any clinical or commercial application is viable.
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The serine/threonine protein kinases CDK2 and GSK-3β are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3β inhibitors targeting breast cancer (<b>5a-g</b>, <b>7a-h</b>, and <b>13a-b</b>). The <i>N<sup>1</sup></i> -unsubstituted oxindole derivatives, <b>series 5</b>, showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds <b>5d-f</b> showed the most potent cytotoxic activity with IC<sub>50</sub> of 3.41, 3.45 and 2.27 μM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 μM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC<sub>50</sub> of 4.81 and 4.34 μM, respectively. On the other hand, the <i>N<sup>1</sup></i> -substituted oxindole derivatives, <b>series 7</b> and <b>13</b>, showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3β enzyme inhibition assay of <b>series 5</b> revealed that compounds <b>5d</b> and <b>5f</b> are showing potent dual CDK2/GSK-3β inhibitory activity with IC<sub>50</sub> of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3β. The most potent compounds <b>5d-f</b> caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3β inhibition. Molecular docking studies showed that the newly synthesised <i>N<sup>1</sup></i> -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3β. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3β. Whereas, in series <b>7</b> and <b>13</b>, the <i>N<sup>1</sup></i> -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.
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DOI: 10.1080/14756366.2020.1862101
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