8USS

IL17A complexed to Compound 7

8USS の概要

• エントリーDOI: 10.2210/pdb8uss/pdb
• 分子名称: Interleukin-17A, 4,5-dichloro-N-[(1S)-1-cyclohexyl-2-{[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]amino}-2-oxoethyl]-1H-pyrrole-2-carboxamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: homodimer, inhibitor, del, cytokine
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15066.18

構造登録者

Argiriadi, M.A.,Ramos, A.L. (登録日: 2023-10-29, 公開日: 2024-04-03, 最終更新日: 2024-10-09)

主引用文献

Ramos, A.L.,Goedken, E.R.,Frank, K.E.,Argiriadi, M.A.,Bazzaz, S.,Bian, Z.,Brown, J.T.C.,Centrella, P.A.,Chen, H.J.,Disch, J.S.,Donner, P.L.,Duignan, D.B.,Gikunju, D.,Greszler, S.N.,Guie, M.A.,Habeshian, S.,Hartl, H.E.,Hein, C.D.,Hutchins, C.W.,Jetson, R.,Keefe, A.D.,Khan, H.,Li, H.Q.,Olszewski, A.,Ortiz Cardona, B.J.,Osuma, A.,Panchal, S.C.,Phelan, R.,Qiu, W.,Shotwell, J.B.,Shrestha, A.,Srikumaran, M.,Su, Z.,Sun, C.,Upadhyay, A.K.,Wood, M.D.,Wu, H.,Zhang, R.,Zhang, Y.,Zhao, G.,Zhu, H.,Webster, M.P.
Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.
J.Med.Chem., 67:6456-6494, 2024

PubMed Abstract: Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.

PubMed: 38574366
DOI: 10.1021/acs.jmedchem.3c02397

実験手法

X-RAY DIFFRACTION (1.47 Å)