Network Pharmacological Analysis through a Bioinformatics Approach of Novel NSC765600 and NSC765691 Compounds as Potential Inhibitors of CCND1/CDK4/PLK1/CD44 in Cancer Types

Simple Summary Around 14 million new cancer cases, rate are reported annually, with high mortality worldswide, several mechanisms are associated with complexities in cancer, which leads to resistance to current therapeutic interventions in cancer patients. The aim of this study was to identify molecular genes responsible for cancer development, progression and resistances to therapeutic intervention, and also evaluate the potency of our novel compounds NSC7565600 and NSC765691 as potential target for these oncogenes. Using bioinformatics, we successfully identified CCND1/CDK4/PLK1/CD44 as oncogenic signatures, which drives cancer progression and resistance to treatment, and as potential druggable candidates for both NSC7565600 and NSC765691 small molecules. We also showed the antiproliferative and cytotoxic effects of these compounds against a panel of NCI-60 cancer cell lines. This suggests the potential of NSC765600 and NSC765691 compounds to inhibit CCND1/CDK4/PLK1/CD44 expressions in cancer. Abstract 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.