Abstract：
: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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Lama L,Adura C,Xie W,Tomita D,Kamei T,Kuryavyi V,Gogakos T,Steinberg JI,Miller M,Ramos-Espiritu L,Asano Y,Hashizume S,Aida J,Imaeda T,Okamoto R,Jennings AJ,Michino M,Kuroita T,Stamford A,Gao P,Meinke P,Glickmandoi
10.1038/s41467-019-08620-4subject
Has Abstractpub_date
2019-05-21 00:00:00pages
2261issue
1issn
2041-1723pii
10.1038/s41467-019-08620-4journal_volume
10pub_type
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