Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization

化学 癌细胞 DNA损伤 车站3 DNA DNA复制 细胞生物学 喹唑啉 G-四倍体 细胞生长 端粒 细胞凋亡 癌症研究 癌症 生物化学 生物 遗传学 立体化学
作者
Ján Jamroškovič,Mara Doimo,Karam Chand,Ikenna Obi,Rajendra Kumar,Kristoffer Brännström,Mattias Hedenström,Rabindra Nath Das,А. А. Ахунзянов,Marco Deiana,Kazutoshi Kasho,Sebastian Sulis Sato,Parham L. Pourbozorgi,James Mason,Paolo Medini,Daniel Öhlund,Sjoerd Wanrooij,Erik Chorell,Nasim Sabouri
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
卷期号:142 (6): 2876-2888 被引量:45
标识
DOI:10.1021/jacs.9b11232
摘要

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.
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