Cyclin D1 (CCND1) and cyclin‐dependent kinase 4 (CDK4) both play significant roles in regulating cell cycle progression, while polo‐like kinase 1 (PLK1) regulates cell differentiation and tumor progression, and activates cancer stem cells (CSCs), with the cluster of differentiation 44 (CD44) surface marker mostly being expressed. These oncogenes have emerged as promoters of metastasis in a variety of cancer types. In this study, we employed comprehensive computational and bioinformatics analyses to predict drug targets of our novel small molecules, NSC765600 and NSC765691, respectively derived from diflunisal and fostamatinib. The target prediction tools identified CCND1/CDK4/PLK1/CD44 as target genes for NSC765600 and NSC765691 compounds. Additionally, the results of our in silico molecular docking analysis showed unique ligand–protein interactions with putative binding affinities of NSC765600 and NSC765691 with CCND1/CDK4/PLK1/CD44 oncogenic signaling pathways. Moreover, we used drug‐likeness precepts as our guidelines for drug design and development, and found that both compounds passed the drug‐likeness criteria of molecular weight, polarity, solubility, saturation, flexibility, and lipophilicity, and also exhibited acceptable pharmacokinetic properties. Furthermore, we used development therapeutics program (DTP) algorithms and identified similar fingerprints and mechanisms of NSC765600 and NSC765691 with synthetic compounds and standard anticancer agents in the NCI database. We found that NSC765600 and NSC765691 displayed antiproliferative and cytotoxic effects against a panel of NCI‐60 cancer cell lines. Based on these finding, NSC765600 and NSC765691 exhibited satisfactory levels of safety with regard to toxicity, and met all of the required criteria for drug‐likeness precepts. Currently, further in vitro and in vivo investigations in tumor‐bearing mice are in progress to study the potential treatment efficacies of the novel NSC765600 and NSC765691 small molecules.
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