Yazar "Abusharkh, Khaled A. N." seçeneğine göre listele

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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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    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.; 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