Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies

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dc.authoridComert Onder, Ferah/0000-0002-4037-1979
dc.authoridSIKIK, Merve/0000-0003-2552-038X
dc.contributor.authorAbusharkh, Khaled A. N.
dc.contributor.authorOnder, Ferah Comert
dc.contributor.authorCinar, Venhar
dc.contributor.authorOnder, Alper
dc.contributor.authorSikik, Merve
dc.contributor.authorHamurcu, Zuhal
dc.contributor.authorOzpolat, Bulent
dc.date.accessioned2025-01-27T20:47:23Z
dc.date.available2025-01-27T20:47:23Z
dc.date.issued2024
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractThe 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
dc.description.sponsorshipAl-Quds University; Council of Higher Education of Turkiye (YOK Palestine Scholarship); Canakkale Onsekiz Mart University Research Coordination Unit [FDK-2022-4145]
dc.description.sponsorshipAl-Quds University; Council of Higher Education of Turkiye (YOK Palestine Scholarship); Canakkale Onsekiz Mart University Research Coordination Unit, Grant/Award Number: FDK-2022-4145
dc.identifier.doi10.1002/ardp.202400504
dc.identifier.issn0365-6233
dc.identifier.issn1521-4184
dc.identifier.issue12
dc.identifier.pmid39318080
dc.identifier.scopus2-s2.0-85204713383
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/ardp.202400504
dc.identifier.urihttps://hdl.handle.net/20.500.12428/24874
dc.identifier.volume357
dc.identifier.wosWOS:001321071500001
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley-V C H Verlag Gmbh
dc.relation.ispartofArchiv Der Pharmazie
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20250125
dc.subjectBenzothiazole
dc.subjectFOXM1 inhibitors
dc.subjectIn vitro
dc.subjectMD simulation
dc.subjectTNBC
dc.titleNovel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies
dc.typeArticle

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