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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (<b>6a–i</b> and <b>9a–f</b>) and carbocycle–indole conjugates (<b>11a</b>,<b>b)</b> as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except <b>6i</b>, <b>9b</b>, and <b>9c</b> efficiently affected the growth of the human breast cancer MCF-7 (IC₅₀: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC₅₀: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds <b>11a</b>,<b>b</b>) diminished the anti-proliferative activity. In addition, hybrids <b>6e</b> and <b>6f</b> displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (<b>6a–h</b>, <b>9a</b>, and <b>9e</b>) were investigated for their potential inhibitory action toward CDK4. Hybrids <b>6a</b> and <b>6e</b> displayed good CDK4 inhibitory activity with IC₅₀s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids <b>6a</b> and <b>6e</b> as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.