9H4D

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

This is a non-PDB format compatible entry.

Summary for 9H4D

• Entry DOI: 10.2210/pdb9h4d/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29035.69

Authors

Rondeau, J.M.,Lehmann, S.,Scheufler, C. (deposition date: 2024-10-18, release date: 2025-01-22, Last modification date: 2025-04-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.117 Å)