9ELX
Crystal Structure of human cyclic GMP-AMP synthase (cGAS) in complex with compound 5; 3-((2-((3-chloro-4-fluorophenyl)amino)-2-oxoethyl)carbamoyl)picolinic acid
This is a non-PDB format compatible entry.
Summary for 9ELX
| Entry DOI | 10.2210/pdb9elx/pdb |
| Descriptor | Cyclic GMP-AMP synthase, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 3-{[2-(3-chloro-4-fluoroanilino)-2-oxoethyl]carbamoyl}pyridine-2-carboxylic acid, ... (6 entities in total) |
| Functional Keywords | human cyclic gmp-amp synthase, amp-pnp compound 5, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43833.37 |
| Authors | |
| Primary citation | Cyr, P.,Fader, L.D.,Burch, J.D.,Pike, K.A.,Sietsema, D.V.,Boily, M.O.,Ciblat, S.,Sgarioto, N.,Skeldon, A.M.,Gaudreault, S.,Le Gros, P.,Dumais, V.,McKay, D.J.J.,Abraham, N.S.,Seliniotakis, R.,Beveridge, R.E. Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization. Acs Med.Chem.Lett., 15:2201-2209, 2024 Cited by PubMed Abstract: Using 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 identified pyrimidine amide compound . Compound is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 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. PubMed: 39691514DOI: 10.1021/acsmedchemlett.4c00471 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.53 Å) |
Structure validation
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