9mdc | pdb_00009mdc
Crystal Structure of human cyclic GMP-AMP synthase (cGAS) in complex with compound 36; (S)-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(2-hydroxyethoxy)pyrimidin-2-yl)methanone
Structural highlights
FunctionCGAS_HUMAN Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production.[1] [2] Publication Abstract from PubMedUsing a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand 23 identified pyrimidine amide compound 36. Compound 36 is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 36 displayed a dose-dependent reduction in cGAMP production in a ConA pharmacodynamic mouse model of acute liver injury, demonstrating potential utility as an in vivo tool compound for further investigation of the cGAS pathway. Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.,Cyr P, Fader LD, Burch JD, Pike KA, Sietsema DV, Boily MO, Ciblat S, Sgarioto N, Skeldon AM, Gaudreault S, Le Gros P, Dumais V, McKay DJJ, Abraham NS, Seliniotakis R, Beveridge RE ACS Med Chem Lett. 2024 Nov 25;15(12):2201-2209. doi: , 10.1021/acsmedchemlett.4c00471. eCollection 2024 Dec 12. PMID:39691514[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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