Abstract B145: Small molecule inhibition of cyclic GMP-AMP synthase reduces interferon expression in macrophages from an autoimmune mouse model

Abstract

Abstract Cyclic GMP-AMP synthase (cGAS) plays a central role in sensing aberrantly localized cytoplasmic dsDNA. Upon binding dsDNA, cGAS synthesizes the cyclic dinucleotide cGAMP, which acts as a second messenger to initiate a signaling pathway for the induction of interferon genes. Given that cytoplasmic DNA can originate from bacteria or virus, cGAS is essential for innate immunity against pathogenic infection. Conversely, cGAS detection of mislocalized nuclear or mitochondrial DNA can lead to hyper-inflammation. Recent studies indicate that cGAS can potentiate autoimmunity in cases of lupus, Aicardi-Goutières syndrome, and other related diseases—suggesting that targeting cGAS activity may be therapeutically beneficial. We report the discovery of a first-in-class generation of cGAS small molecule inhibitor, RU.365, identified in a high-throughput screen. Its structure-activity relationship, and selectivity and potency in cellular assays, was characterized. Moreover, we solved the structure of cGAS in complex with dsDNA and RU.365 or its close structural analog within the active site. Finally, we demonstrate that the inhibitor can reduce constitutive expression of interferonin macrophages derived from a mouse model of autoimmunity. RU.365 will be useful towards understanding the biological roles of cGAS and can serve as a molecular scaffold for development of future autoimmune therapies. Note: This abstract was not presented at the conference. Citation Format: Pu Gao. Small molecule inhibition of cyclic GMP-AMP synthase reduces interferon expression in macrophages from an autoimmune mouse model [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B145.