9FL3

Crystal structure of IL-17A in complex with compound 26

This is a non-PDB format compatible entry.

Summary for 9FL3

• Entry DOI: 10.2210/pdb9fl3/pdb
• Descriptor: Interleukin-17A, (~{E})-~{N}-[(~{S})-[4,4-bis(fluoranyl)cyclohexyl]-[7-[(1~{S})-2-methoxy-1-[(4~{S})-2-oxidanylidene-4-(trifluoromethyl)imidazolidin-1-yl]ethyl]imidazo[1,2-b]pyridazin-2-yl]methyl]-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: 29090.66

Authors

Rondeau, J.M.,Lehmann, S.,Scheufler, C. (deposition date: 2024-06-04, release date: 2024-10-02, Last modification date: 2024-10-09)

Primary citation

Velcicky, J.,Bauer, M.R.,Schlapbach, A.,Lapointe, G.,Meyer, A.,Vogtle, M.,Blum, E.,Ngo, E.,Rolando, C.,Nimsgern, P.,Teixeira-Fouchard, S.,Lehmann, H.,Furet, P.,Berst, F.,Schumann, J.,Stringer, R.,Larger, P.,Schmid, C.,Prendergast, C.T.,Riek, S.,Schmutz, P.,Lehmann, S.,Berghausen, J.,Scheufler, C.,Rondeau, J.M.,Burkhart, C.,Knoepfel, T.,Gommermann, N.
Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and alpha-Fluoroacrylate Containing IL-17 Inhibitors.
J.Med.Chem., 67:16692-16711, 2024

PubMed Abstract: IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds ( and ) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.

PubMed: 39276085
DOI: 10.1021/acs.jmedchem.4c01520

Experimental method

X-RAY DIFFRACTION (2.068 Å)