%0 Journal Article
%T Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease
%A Song Jia
%A Yang Rui-rui
%A Chang Jie
%A Liu Ya-dan
%A Lu Cheng-hao
%A Chen Li-fan
%A Guo Hao
%A Zhang Ying-hui
%A Fan Zi-sheng
%A Zhou Jing-yi
%A Zhou Gui-zhen
%A Zhang Ke-ke
%A Luo Xiao-min
%A Chen Kai-xian
%A Jiang Hua-liang
%A Zhang Su-lin
%A Zheng Ming-yue
%J Acta Pharmacologica Sinica
%D 2023
%B 2023
%9 
%! Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease
%K 
%X 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.
%U http://www.chinaphar.com/article/view/10804
%V 44
%N 4
%P 791–800
%@ 1745-7254