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

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.

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

“…The anti-cancer activity of fostamatinib was also evident against head and neck squamous cell carcinoma [103], hepatocellular carcinoma [104], breast cancer [105], and diffuse large B cell lymphoma [106] cell lines. Moreover, a fostamatinib derivative, NSC765691, also exhibited antiproliferative activity against the panel of NCI-60 cell lines [107]. The drug was also shown to have significant clinical activity when treating non-Hodgkin lymphoma and chronic lymphocytic leukemia patients [108].…”

Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures

“…Potential SJ10 target genes were predicted using an open-source web tool based on the Prediction of Biological Activity Spectra (PASS) [ 44 ] ( , accessed on 17 August 2021). In addition, we explored the Swiss target prediction tool ( , accessed on 17 August 2021), a web-based algorithm that uses the principle of similarity to predict drug targets of bioactive small molecules [ 45 , 46 ] as an independent tool to further validate the predicted potential target genes of SJ10 ( Table 1 ).…”

Bioinformatics screening of colorectal-cancer causing molecular signatures through gene expression profiles to discover therapeutic targets and candidate agents

“…By this time, several authors have suggested different sets of key genes (KGs) to explore molecular mechanisms and pathogenetic processes of CRC progression [ 14 – 45 ] in which some studies have employed multiple datasets to identify CRC-causing KGs [ 15 – 17 , 22 , 25 , 26 , 31 , 32 , 37 , 40 – 43 , 46 – 49 ]. Few studies also explored their suggested KGs-guided candidate drug molecules for the treatment against CRC [ 14 , 37 , 40 – 42 , 50 – 59 ]. However, their published data did not display any common KGs as well as common drug molecules (see Additional file 1 : Table S1) in all studies.…”