Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.
Bin ShanHui HouKeke ZhangRui LiChang ShenZhengyang ChenPeijia XuRongrong CuiZhaoming SuChangfa ZhangRuirui YangGuizhen ZhouYadan LiuHao GuoKaixian ChenWei FuHualiang JiangSulin ZhangMingyue ZhengPublished in: Journal of medicinal chemistry (2023)
The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC 50 = 0.38 ± 0.03 μM) and mouse RAW 264.7 cells (EC 50 = 12.94 ± 1.78 μM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.
Keyphrases
- infectious diseases
- signaling pathway
- induced apoptosis
- dendritic cells
- endothelial cells
- genome wide
- papillary thyroid
- single cell
- epithelial mesenchymal transition
- stem cells
- gene expression
- cell therapy
- immune response
- oxidative stress
- cell cycle arrest
- bioinformatics analysis
- genome wide identification
- mesenchymal stem cells
- binding protein
- combination therapy
- smoking cessation
- oxide nanoparticles