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Quinazoline Ligands...
Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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- Jamroskovic, Jan (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Doimo, Mara (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Chand, Karam (author)
- Umeå universitet,Kemiska institutionen
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- Obi, Ikenna (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Kumar, Rajendra (author)
- Umeå universitet,Institutionen för fysik,Kemiska institutionen
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- Brännström, Kristoffer (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Hedenström, Mattias, 1976- (author)
- Umeå universitet,Kemiska institutionen
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- Das, Rabindra Nath (author)
- Umeå universitet,Kemiska institutionen
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- Akhunzianov, Almaz (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik,Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
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- Deiana, Marco (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Kasho, Kazutoshi (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Sulis Sato, Sebastian (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Pourbozorgi-Langroudi, Parham (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Mason, James E. (author)
- Umeå universitet,Onkologi
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- Medini, Paolo (author)
- Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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- Öhlund, Daniel, 1979- (author)
- Umeå universitet,Onkologi
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- Wanrooij, Sjoerd (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Chorell, Erik (author)
- Umeå universitet,Kemiska institutionen
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- Sabouri, Nasim (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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(creator_code:org_t)
- 2020-01-28
- 2020
- English.
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:6, s. 2876-2888
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https://umu.diva-por... (primary) (Raw object)
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- NATURVETENSKAP -- Fysik -- Atom- och molekylfysik och optik (hsv//swe)
- NATURAL SCIENCES -- Physical Sciences -- Atom and Molecular Physics and Optics (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Jamroskovic, Jan
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Doimo, Mara
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Chand, Karam
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Obi, Ikenna
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Kumar, Rajendra
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Brännström, Kris ...
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show more...
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Hedenström, Matt ...
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Das, Rabindra Na ...
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Akhunzianov, Alm ...
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Deiana, Marco
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Kasho, Kazutoshi
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Sulis Sato, Seba ...
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Pourbozorgi-Lang ...
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Mason, James E.
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Medini, Paolo
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Öhlund, Daniel, ...
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Wanrooij, Sjoerd
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Chorell, Erik
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Sabouri, Nasim
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Physical Science ...
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and Atom and Molecul ...
- Articles in the publication
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Journal of the A ...
- By the university
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Umeå University