9FL3

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

これはPDB形式変換不可エントリーです。

9FL3 の概要

• エントリーDOI: 10.2210/pdb9fl3/pdb
• 分子名称: 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)
• 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: 29090.66

構造登録者

Rondeau, J.M.,Lehmann, S.,Scheufler, C. (登録日: 2024-06-04, 公開日: 2024-10-02, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.068 Å)