8USR

IL17A homodimer complexed to Compound 23

Summary for 8USR

• Entry DOI: 10.2210/pdb8usr/pdb
• Descriptor: Interleukin-17A, ~{N}-[(2~{S})-1-[[(1~{S})-1-(8~{a}~{H}-imidazo[1,2-a]pyrimidin-2-yl)ethyl]amino]-1-oxidanylidene-4-phenyl-butan-2-yl]-4,5-bis(chloranyl)-1~{H}-pyrrole-2-carboxamide (3 entities in total)
• Functional Keywords: homodimer, inhibitor, del, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 60090.84

Authors

Argiriadi, M.A.,Ramos, A.L. (deposition date: 2023-10-29, release date: 2024-04-03, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.83 Å)