9MDC

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

This is a non-PDB format compatible entry.

Summary for 9MDC

• Entry DOI: 10.2210/pdb9mdc/pdb
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION, [(1S)-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, ... (6 entities in total)
• Functional Keywords: human cyclic gmp-amp synthase amp-pnp compound 36, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43902.93

Authors

Sietsema, D.V. (deposition date: 2024-12-05, release date: 2025-01-01)

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

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: 39691514
DOI: 10.1021/acsmedchemlett.4c00471

Experimental method

X-RAY DIFFRACTION (1.25 Å)