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

これはPDB形式変換不可エントリーです。

9ELX の概要

• エントリーDOI: 10.2210/pdb9elx/pdb
• 分子名称: 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)
• 機能のキーワード: human cyclic gmp-amp synthase, amp-pnp compound 5, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43833.37

構造登録者

Sietsema, D.V. (登録日: 2024-12-05, 公開日: 2025-01-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.53 Å)