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Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0001-6871-7663
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-7691-4392
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0003-0364-8964
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Number of Authors: 192020 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed) Published
Abstract [en]

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

Place, publisher, year, edition, pages
2020. Vol. 142, no 6, p. 2876-2888
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Atom and Molecular Physics and Optics
Identifiers
URN: urn:nbn:se:umu:diva-169314DOI: 10.1021/jacs.9b11232ISI: 000514255300025PubMedID: 31990532Scopus ID: 2-s2.0-85079045732OAI: oai:DiVA.org:umu-169314DiVA, id: diva2:1420700
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe Foundations, SMK-1632Åke Wiberg FoundationSwedish Cancer SocietyVästerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001EU, Horizon 2020, 751474Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2023-03-24Bibliographically approved

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Jamroskovic, JanDoimo, MaraChand, KaramObi, IkennaKumar, RajendraBrännström, KristofferHedenström, MattiasDas, Rabindra NathAkhunzianov, AlmazDeiana, MarcoKasho, KazutoshiSulis Sato, SebastianPourbozorgi-Langroudi, ParhamMason, James E.Medini, PaoloÖhlund, DanielWanrooij, SjoerdChorell, ErikSabouri, Nasim

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Jamroskovic, JanDoimo, MaraChand, KaramObi, IkennaKumar, RajendraBrännström, KristofferHedenström, MattiasDas, Rabindra NathAkhunzianov, AlmazDeiana, MarcoKasho, KazutoshiSulis Sato, SebastianPourbozorgi-Langroudi, ParhamMason, James E.Medini, PaoloÖhlund, DanielWanrooij, SjoerdChorell, ErikSabouri, Nasim
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Department of Medical Biochemistry and BiophysicsDepartment of ChemistryDepartment of PhysicsOncologyDepartment of Integrative Medical Biology (IMB)
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Journal of the American Chemical Society
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Atom and Molecular Physics and Optics

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