Nature Communications, May, 2019， DOI: http://dx.doi.org/10.1038/s41467-019-08620-4
Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression
Lodoe Lama, Carolina Adura, Wei Xie, Daisuke Tomita, Taku Kamei, Vitaly Kuryavyi, Tasos Gogakos, Joshua I. Steinberg, Michael Miller,
Lavoisier Ramos-Espiritu, Yasutomi Asano, Shogo Hashizume, Jumpei Aida, Toshihiro Imaeda, Rei Okamoto, Andy J. Jennings, Mayako Michino, Takanobu Kuroita, Andrew Stamford, Pu Gao, Peter Meinke, J. Fraser Glickman, Dinshaw J. Patel & Thomas Tuschl
Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.