16588-06-0Relevant articles and documents
Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists
Xi, Qiumu,Wang, Mingjin,Jia, Wenqiang,Yang, Mingjian,Hu, Jinping,Jin, Jing,Chen, Xiaoguang,Yin, Dali,Wang, Xiaojian
, p. 260 - 282 (2020)
Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds 16g, 24b, and 24e were measured by a STING competition binding assay. A more thorough study of the effect on the STING signaling pathway demonstrated that three compounds, 16g, 24b, and 24e, significantly increased the protein levels and mRNA levels of IFN-β, CXCL10, and IL-6, and 24b as a representative compound effectively triggered the phosphorylation of STING, TBK1, and IRF3 in both human peripheral blood mononuclear cells (hPBMCs) and WT THP-1 cells. In addition, compound 24b demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. Furthermore, the pharmacokinetic profile of compound 24b was fully evaluated.
STING HETEROCYCLE AGONISTS AND USES THEREOF
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Paragraph 00338, (2020/07/14)
The present invention provides compounds, compositions thereof, and methods of using the same for the modulation of STING, and the treatment of STING-mediated disorders.
Synthesis and evaluation of sulfonylnitrophenylthiazoles (SNPTs) as thyroid hormone receptor-coactivator interaction inhibitors
Hwang, Jong Yeon,Attia, Ramy R.,Zhu, Fangyi,Yang, Lei,Lemoff, Andrew,Jeffries, Cynthia,Connelly, Michele C.,Guy, R. Kiplin
experimental part, p. 2301 - 2310 (2012/05/21)
We previously identified a series of methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its coactivators. MSNBs inhibit coactivator binding through irreversible modification of cysteine 298 of the thyroid hormone receptor (TR). Although MSNBs have better pharmacological features than our first generation inhibitors (β-aminoketones), they contain a potentially unstable ester linkage. Here we report the bioisosteric replacement of the ester linkage with a thiazole moiety, yielding sulfonylnitrophenylthiazoles (SNPTs). An array of SNPTs representing optimal side chains from the MSNB series was constructed using parallel chemistry and evaluated to test their antagonism of the TR-coactivator interaction. Selected active compounds were evaluated in secondary confirmatory assays including regulation of thyroid response element driven transcription in reporter constructs and native genes. In addition the selected SNPTs were shown to be selective for TR relative to other nuclear hormone receptors (NRs).