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Öğe A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells(Humana Press Inc, 2024) Abusharkh, Khaled A. N.; Cömert Önder, Ferah; Çınar, Venhar; Hamurcu, Zuhal; Özpolat, Bülent; Ay, MehmetFOXM1, 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.Öğe Delivery of Small Molecule EF2 Kinase Inhibitor for Breast and Pancreatic Cancer Cells Using Hyaluronic Acid Based Nanogels(Springer/Plenum Publishers, 2020) Cömert Önder, Ferah; Sağbaş Suner, Selin; Şahiner, Nurettin; Ay, Mehmet; Özpolat, BülentPurpose To evalauted natural polymeric biomaterials including hyaluronic acid (HA) and its copolymeric form HA:Suc nanoparticles (NPs) as drug carrier systems for delivery of hydrophobic small molecule kinase EF2-kinase inhibitor in breast and pancreatic cancer cells. Methods In vitro cellular uptake studies of Rhodamine 6G labaled HA:Suc nanoparticles were evaluated by using flow cytometry analysis and fluorescent microscopy in breast (MDA-MB-231 and MDA-MB-436) and pancreatic cancer cells (PANC-1 and MiaPaca-2). Besides, in vitro release study of compound A (an EF2-kinase inhibitor) as a model hydrophobic drug was performed in the cancer cells. Results These biological evaluation studies indicated that HA and HA:Suc NPs provided a highly effective delivery of compound A were into breast and pancreatic cancer cells, leading to significant inhibition of cell proliferation and colony formation of breast and pancreatic cancer cells. Conclusion HA-sucrose NPs incorporating an EF2-Kinase inhibitor demonstrate significant biologic activity in breast and pancreatic cancer cells. This is the first study that shows natural polymeric drug carriers succesfully deliver a hydrofobic cancer drug into cancer cells. Nanoparticles based on HA:Suc are effective in delivering hydrofobic cancer drugs in breast and pancreatic cancers.Öğe Hyaluronic acid and hyaluronic acid: Sucrose nanogels for hydrophobic cancer drug delivery(Elsevier Science Bv, 2019) Sağbaş Suner, Selin; Ari, Betül; Cömert Önder, Ferah; Özpolat, Bülent; Ay, Mehmet; Şahiner, NurettinPorous and biodegradable hyaluronic acid (HA) nanogel and their copolymeric forms with sucrose (Suc), HA:Sucrose (HA:Suc) nanogels, were synthesized by employing glycerol diglycidyl ether (GDE) as crosslinker with a single step reaction in surfactant-free medium. The size of the nanogels was determined as 150 +/- 50 nm in dried state from SEM images and found to increase to about 540 +/- 47 nm in DI water measured with DLS measurements. The surface areas of HA and HA:Suc nanogels were measured as 18.07 +/- 2.4 and 32.30 +/- 6.1 m(2)/g with porosities of 3.58 +/- 1.8, and 9.44 +/- 3.1 nm via BET analysis, respectively. The zeta potentials for HA and HA:Suc nanogels were measured as -33 +/- 1.4 and -30 +/- 1.2 mV, respectively. The thermal degradation of both types of nanogels revealed similar trends, while hydrolytic degradation of the nanogels was about 22.7 +/- 02 wt% in 15 days. Both HA and HA:Suc nanogels were stable in blood up to 250 mu g/mL concentration with approximately 0.5 +/- 0.1% hemolysis ratio and 76 +/- 12% blood clotting indices, respectively. Finally, these nanogels were used as a sustained slow-release or long-term delivery system over 2 days for a hydrophobic cancer drug, 3-((E)-3-(4-hydroxyphenyl)acryloyl)-2H-chromen-2-on (A(#)) established by our group. The nanogels successfully delivered the model drug A at 10.43 +/- 2.12 mg/g for 2 days. (C) 2019 Elsevier B.V. All rights reserved.Öğe In vitro drug release studies for the treatment of TNBC and pancreatic cancers from natural derivated polymeric micro- and nano-particles(Amer Chemical Soc, 2018) Cömert Önder, Ferah; Sağbaş, Selin; Ay, Mehmet; Özpolat, Bülent; Şahiner, Nurettin[Anstract Not Available]Öğe 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.; Cömert Önder, Ferah; Çınar, Venhar; Önder, Alper; Sıkık, Merve; Hamurcu, Zuhal; Özpolat, Bülent; Ay, MehmetThe 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
