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    A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells
    (Humana Press Inc, 2024) Abusharkh, Khaled A. N.; Onder, Ferah Comert; Cinar, Venhar; Hamurcu, Zuhal; Ozpolat, Bulent; Ay, Mehmet
    FOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 mu M in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 mu M and in BT-20 cells and at 70 mu M in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.
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    Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors
    (Amer Chemical Soc, 2020) Onder, Ferah Comert; Durdagi, Serdar; Sahin, Kader; Ozpolat, Bulent; Ay, Mehmet
    Eukaryotic elongation factor-2 kinase (eEF-2K) is an unusual alpha kinase commonly upregulated in various human cancers, including breast, pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K is relevant to poor prognosis and shorter patient survival in breast and lung cancers and validated it as a molecular target using genetic methods in related in vivo tumor models. Although several eEF-2K inhibitors have been published, none of them have shown to be potent and specific enough for translation into clinical trials. Therefore, development of highly effective novel inhibitors targeting eEF-2K is needed for clinical applications. However, currently, the crystal structure of eEF-2K is not known, limiting the efforts for designing novel inhibitor compounds. Therefore, using homology modeling of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides including compounds A1, A2, and B1-B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast cancer cells. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1-B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 mu M concentrations compared to compounds B1-B4, supporting the in silico findings. In conclusion, the results of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic applications.
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    New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor
    (Amer Assoc Cancer Research, 2019) Onder, Ferah Comert; Ay, Mehmet; Durdagi, Serdar; Ozpolat, Bulent; Kantarcioglu, Isik
    [Anstract Not Available]
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    Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies
    (Wiley-V C H Verlag Gmbh, 2024) Abusharkh, Khaled A. N.; Onder, Ferah Comert; Cinar, Venhar; Onder, Alper; Sikik, Merve; Hamurcu, Zuhal; Ozpolat, Bulent
    The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC50 values of 6.13, 10.77, and 12.86 mu M, respectively, versus 20.79 mu M for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies. The oncogenic transcription factor FOXM1, overexpressed in breast and other cancers, drives tumor growth, making it a key therapeutic target, but existing inhibitors lack specificity and potency. Among the synthesized benzothiazole derivatives (KC10-KC13) and benzothiazole-thiazolidine-2,4-dione hybrids (KC21-KC36), KC12, KC21, and KC30 significantly inhibited FOXM1 in MDA-MB-231 cells at lower concentrations compared to FDI-6. image
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    Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy
    (Royal Soc Chemistry, 2022) Onder, Ferah Comert; Siyah, Pinar; Durdagi, Serdar; Ay, Mehmet; Ozpolat, Bulent
    Eukaryotic elongation factor 2 kinase (eEF2K) has been shown to be an important molecular driver of tumorigenesis and validated as a potential novel molecular target in various solid cancers including triple negative breast cancer (TNBC). Therefore, there has been significant interest in identifying novel inhibitors of eEF2K for the development of targeted therapeutics and clinical translation. Herein, we investigated the effects of indole ring containing derivatives of etodolac, a nonsteroidal anti-inflammatory (NSAID) drug, as potential eEF2K inhibitors and we designed and synthesized seven novel compounds with a pyrano[3,4-b] indole core structure. We evaluated the eEF2K inhibitory activity of seven of these novel compounds using in silico molecular modeling and in vitro studies in TNBC cell lines. We identified two novel compounds (EC1 and EC7) with significant in vitro activity in inhibiting eEF2K in TNBC cells. In conclusion, our studies indicate that pyrano[3,4-b] indole scaffold containing compounds demonstrate marked eEF2K inhibitory activity and they may be used as eEF2K inhibitors for the development of eEF2K-targeted therapeutics.
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    Structure prediction of eukaryotic elongation factor-2 kinase and identification of the binding mechanisms of its inhibitors: homology modeling, molecular docking, and molecular dynamics simulation
    (Taylor & Francis Inc, 2022) Tatar, Gizem; Tok, Tugba Taskin; Ozpolat, Bulent; Mehmet, A. Y.
    Protein kinases emerged as one of the most successful families of drug targets due to their increased activity and involvement in mediating critical signal transduction pathways in cancer cells. Recent evidence suggests that eukaryotic elongation factor 2 kinase (eEF-2K) is a potential therapeutic target for treating some highly aggressive solid cancers, including lung, pancreatic and triple-negative breast cancers. Thus, several compounds have been developed for the inhibition of the enzyme activity, but they are not sufficiently specific and potent. Besides, the crystal structure of this kinase remains unknown. Hence, the functional organization and regulation of eEF-2K remain poorly characterized. For this purpose, we constructed a homology model of eEF-2K and then used docking methodology to better understanding the binding mechanism of eEF-2K with 58 compounds that have been proposed as existing inhibitors. The results of this analysis were compared with the experimental results and the compounds effective against eEF-2K were determined against eEF-2K as a result of both studies. And finally, molecular dynamics (MD) simulations were performed for the stability of eEF-2K with these compounds. According to these study defined that the binding mechanism of eEF-2K with inhibitors at the molecular level and elucidated the residues of eEF-2K that play an important role in enzyme selectivity and ligand affinity. This information may lead to new selective and potential drug molecules to be for inhibition of eEF-2K.