This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer ...therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound
exhibited the highest CDK9 inhibition with an IC
of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC
values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound
showed the highest antiviral potency with an IC
of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that
displayed a good affinity to proteases. The result of the docking studies of
with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.
Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to ...modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ (Ca2+i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.
Rhododendron arboreum: Sm., also known as Burans is traditionally used as an anti-inflammatory, anti-diabetic, hepatoprotective, adaptogenic, and anti-oxidative agent. It has been used since ancient ...times in Indian traditional medicine for various liver disorders. However, the exact mechanism behind its activity against NAFLD is not known. The aim of the present study is to investigate the molecular mechanism of Rhododendron arboreum flower (RAF) in the treatment of NAFLD using network pharmacology and molecular docking methods. Bioactives were also predicted for their drug-likeness score, probable side effects and ADMET profile. Protein-protein interaction (PPI) data was obtained using the STRING platform. For the visualisation of GO analysis, a bioinformatics server was employed. Through molecular docking, the binding affinity between potential targets and active compounds were assessed. A total of five active compounds of RAF and 30 target proteins were selected. The targets with higher degrees were identified through the PPI network. GO analysis indicated that the NAFLD treatment with RAF primarily entails a response to the fatty acid biosynthetic process, lipid metabolic process, regulation of cell death, regulation of stress response, and cellular response to a chemical stimulus. Molecular docking and molecular dynamic simulation exhibited that rutin has best binding affinity among active compounds and selected targets as indicated by the binding energy, RMSD, and RMSF data. The findings comprehensively elucidated toxicity data, potential targets of bioactives and molecular mechanisms of RAF against NAFLD, providing a promising novel strategy for future research on NAFLD treatment.
Currently, drug resistance to commercially available antibiotics is imparting negative consequences to global health, and the development of novel antibiotics in a timely manner is a prime need of ...the hour. In the current study, an e-pharmacophore model was built using the 3D structure of DNA gyrase in complex with a standard inhibitor. The generated model was subjected to a pharmacophore based virtual screening against 45,257,086 molecules having 223,460,579 conformers available in MCULE database. Pharmacophore based screening retrieved eight molecules as top hit based on pharmacophoric features in comparison to standard inhibitors. Afterward, all eight compounds were subjected molecular docking based on deep learning algorithm. The molecular docking revealed that compound MCULE-6042843173 and MCULE-2362244223 had significant binding orientation inside active pocket of targeted protein with binding affinity of −9.52 and −9.24 kcal/mol respectively. In addition, density functional theory studies (DFT) were performed to evaluate quantum mechanics of top ranked compounds which were investigated through quantum mechanics (QM) computations which strongly assisted the findings of other in-silico investigations. Consequently, the MCULE-6042843173 and MCULE-2362244223 were subjected to MD simulation studies for evaluation of stability, hydrogen bond analysis, van der Waals interactions, and the contact profile of compounds with targeted amino acid residues. Findings of current study suggested MCULE-6042843173 and MCULE-2362244223 as potential and novel inhibitor of DNA Gyrase enzyme.
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•Pharmacophore based virtual screening of MCULE data base.•Deep learning based molecular docking against DNA gyrase B.•QM/MM computations of top ranked hits and protein ligand complexes.•Molecular Dynamics simulations.•ADMET prediction of top ranked hits.
Abstract
Triple-negative subtype of breast cancer (TNBC) contains exclusively tumorigenic and often endowed with self-renewing and resistance to cytotoxic chemotherapy, such as, paclitaxel resulting ...in relative increases in CSCs phenotype. Signaling through NF-kB may be essential for the CSCs self-renewal and could present potential target for novel treatment in breast cancer patients. We explored the possible involvement of NF-kB pathway that contribute to the functions and maintenance of breast CSCs and targeting this pathway by cisplatin combining with a natural product eugenol both in vitro and in vivo, using estrogen dependent (MCF-7) and independent (MDA-MB-231, MDA-MB-468 and BT-20) cell lines and xenografted both subcutaneous and orthotopic (fat pad) sites in nude mice. Chromatin immunoprecipitation (ChIP) assay was utilized to assess the NF-kB associated DNA binding capacity in promoter region. Surprisingly, neither cisplatin nor eugenol was capable of complete diminishing the CSCs populations. Cisplatin alone administration partially diminished apoptosis, mammospheres formation, aldehyde dehydrogenase 1 (ALDH1) activity, invasion and growth on nude mice. We observed cisplatin-induced activation of NF-kB associated with survival and regrowth of mamospheres. For effective elimination of CSCs phenotype by cisplatin, we cotreated cells with eugenol. Combination of eugenol and cisplatin significantly eradicated cisplatin induced NF-kB DNA binding capability assed by EMSA and ChIP assays, which was associated with abrogated apoptosis, mammospheres formation, ALDH1 activity and invasion. In vivo, combination therapy reduced the tumor size in synergistic manner. This was possibly due to induction of apoptosis, inhibition of proliferation, angiogenesis and downregulation of cisplatin-induced expression of proteins of NF-kB target genes. Although treatment of mammospheres by cisplatin partially induced the CSCs population through interleukin (IL)-6 pathway, however, only coadministration of eugenol and cisplatin reduced the numbers of CSCs to virtually undeletable levels in vitro and in vivo. Our data suggest that eugenol may be well suited to increase targeting of breast CSCs by cisplatin.
Citation Format: Syed S. Islam, Al-Sharif Ibtehaj, Sultan Ahlam, Abdelilah Aboussekhra. Eugenol potentiates the effect of cisplatin on cancer stem-like cells through targeting the NF-κB pathway. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2907.
Triple‐negative breast tumors are very aggressive and contain relatively high proportion of cancer stem cells, and are resistant to chemotherapeutic drugs including cisplatin. To overcome these ...limitations, we combined eugenol, a natural polyphenolic molecule, with cisplatin to normalize cisplatin mediated toxicity and potential drug resistance. Interestingly, the combination treatment provided significantly greater cytotoxic and pro‐apoptotic effects as compared to treatment with eugenol or cisplatin alone on several triple‐negative breast cancer cells both in vitro and in vivo. Furthermore, adding eugenol to cisplatin potentiated the inhibition of breast cancer stem cells by inhibiting ALDH enzyme activity and ALDH‐positive tumor initiating cells. We provide also clear evidence that eugenol potentiates cisplatin inhibition of the NF‐κB signaling pathway. Indeed, the binding of NF‐κB to its cognate binding sites present in the promoters of IL‐6 and IL‐8 was dramatically reduced, which led to potent down‐regulation of the IL‐6 and IL‐8 cytokines upon combination treatment relative to the single agents. Similar effects were observed on proliferation, inhibition of epithelial‐to‐mesenchymal transition and stemness markers in tumor xenografts. These results provide strong preclinical justification for combining cisplatin with eugenol as therapeutic approach for triple‐negative breast cancers through targeting the resistant ALDH‐positive cells and inhibiting the NF‐κB pathway.
AKR1B1 and AKR1B10 are important members of aldo–keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various ...metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule’s reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of − 30.84 and − 29.36 kJ/mol respectively. To validate the stability of the protein–ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.
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