9SR8

Crystal structure of IL-17A in complex with compound 22

This is a non-PDB format compatible entry.

Summary for 9SR8

• Entry DOI: 10.2210/pdb9sr8/pdb
• Related: 9SQI
• Descriptor: Interleukin-17A, ~{N}-[(~{S})-[3-[[7-bromanyl-3-methyl-2,4-bis(oxidanylidene)quinazolin-1-yl]methyl]-1~{H}-1,2,4-triazol-5-yl]-cyclohexyl-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide (3 entities in total)
• Functional Keywords: inhibitor, complex, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29059.52

Authors

Rondeau, J.M.,Lehmann, S.,Scheufler, C. (deposition date: 2025-09-24, release date: 2025-12-17, Last modification date: 2026-01-07)

Primary citation

Bauer, M.R.,Velcicky, J.,Goetz, A.,Furet, P.,Nimsgern, P.,Tichkule, R.,Schlapbach, A.,Meyer, A.,Vogtle, M.,Rolando, C.,Lehmann, H.,Berst, F.,Riek, S.,Schmutz, P.,Lehmann, S.,Scheufler, C.,Rondeau, J.M.,Burkhart, C.,Gommermann, N.,Knoepfel, T.
Harnessing Glutamine-117 Plasticity toward Structure-Based Identification of Triazole IL-17 Inhibitors.
J.Med.Chem., 68:26494-26512, 2025

PubMed Abstract: The proinflammatory cytokine IL-17 is crucial for host defense but has also been linked to various inflammatory and autoimmune diseases. Antibody-based IL-17 inhibitors like secukinumab (Cosentyx) have demonstrated clinical success in psoriasis, psoriatic arthritis, and ankylosing spondylitis, sparking efforts to develop orally bioavailable small molecule alternatives. However, most small molecule IL-17 inhibitors failed in preclinical and clinical stages due to safety concerns and other challenges. This work describes the discovery of a 1,2,4-triazole scaffold that acts as an amide bioisostere. Its unique vector toward the Trp90 pocket, a key cavity for ligand binding, required the development of novel motifs. A structure-based library approach, considering the high plasticity of the Gln117 side chain, yielded structurally diverse Trp90 pocket binding motifs. The X-ray structures of the most potent hits guided subsequent optimization, resulting in triazole-based IL-17 inhibitors with low nanomolar cellular activity, which are promising leads for further development.

PubMed: 41355177
DOI: 10.1021/acs.jmedchem.5c02794

Experimental method

X-RAY DIFFRACTION (2.565 Å)