716-11-0Relevant articles and documents
Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
?hlund, Daniel,Akhunzianov, Almaz,Br?nnstr?m, Kristoffer,Chand, Karam,Chorell, Erik,Deiana, Marco,Doimo, Mara,Hedenstr?m, Mattias,Jamroskovic, Jan,Kasho, Kazutoshi,Kumar, Rajendra,Mason, James E.,Medini, Paolo,Nath Das, Rabindra,Obi, Ikenna,Pourbozorgi, Parham L.,Sabouri, Nasim,Sulis Sato, Sebastian,Wanrooij, Sjoerd
supporting information, (2020/02/13)
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.
Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure
Soubhye, Jalal,Chikh Alard, Ibaa,Aldib, Iyas,Prévost, Martine,Gelbcke, Michel,De Carvalho, Annelise,Furtmüller, Paul G.,Obinger, Christian,Flemmig, J?rg,Tadrent, Sara,Meyer, Franck,Rousseau, Alexandre,Nève, Jean,Mathieu, Véronique,Zouaoui Boudjeltia, Karim,Dufrasne, Fran?ois,Van Antwerpen, Pierre
, p. 6563 - 6586 (2017/08/17)
The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.
Compounds for the treatment of pain
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, (2008/06/13)
This invention provides methods of treating pain, urinary incontinence and other abnormalities mediated by a NPFF receptor, which comprises administering to a subject a therapeutically effective amount of a chemical compound which acts at the NPFF1 receptor, the NPFF2 receptor, or at both the NPFF1 and NPFF2 receptors.
