9H4D

Crystal structure of IL-17A in complex with compound 18

これはPDB形式変換不可エントリーです。

9H4D の概要

• エントリーDOI: 10.2210/pdb9h4d/pdb
• 分子名称: Interleukin-17A, (E)-N-[(1S)-1-[4,4-bis(fluoranyl)cyclohexyl]-2-oxidanylidene-2-[[5-[(2-oxidanylidene-3H-benzimidazol-1-yl)methyl]-1,3-thiazol-2-yl]amino]ethyl]-3-cyclopropyl-2-fluoranyl-prop-2-enamide (3 entities in total)
• 機能のキーワード: inhibitor, complex, cytokine
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29035.69

構造登録者

Rondeau, J.M.,Lehmann, S.,Scheufler, C. (登録日: 2024-10-18, 公開日: 2025-01-22, 最終更新日: 2025-04-16)

主引用文献

Velcicky, J.,Ngo, E.,Bauer, M.R.,Meyer, A.,Schlapbach, A.,Racine, S.,Orain, D.,Pflieger, D.,Teixeira-Fouchard, S.,Dubois, C.,Goetz, A.,Steiner, R.,Palmieri, M.,Bussenault, A.,Stringer, R.,Larger, P.,Riek, S.,Schmutz, P.,Lehmann, S.,Scheufler, C.,Rondeau, J.M.,Burkhart, C.,Knoepfel, T.,Gommermann, N.
Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing.
Chemmedchem, 20:e202400851-e202400851, 2025

PubMed Abstract: The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e. g. secukinumab (Cosentyx). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day.

PubMed: 39715021
DOI: 10.1002/cmdc.202400851

実験手法

X-RAY DIFFRACTION (2.117 Å)