How to cite item

Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease

   
@article{APS10804,
	author = {Jia Song and Rui-rui Yang and Jie Chang and Ya-dan Liu and Cheng-hao Lu and Li-fan Chen and Hao Guo and Ying-hui Zhang and Zi-sheng Fan and Jing-yi Zhou and Gui-zhen Zhou and Ke-ke Zhang and Xiao-min Luo and Kai-xian Chen and Hua-liang Jiang and Su-lin Zhang and Ming-yue Zheng},
	title = {Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease},
	journal = {Acta Pharmacologica Sinica},
	volume = {44},
	number = {4},
	year = {2023},
	keywords = {},
	abstract = {Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10804}
}