9NA6

IRAK4 in Complex with Compound 34

This is a non-PDB format compatible entry.

Summary for 9NA6

• Entry DOI: 10.2210/pdb9na6/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, (6P)-4-{[(1S)-1-cyanoethyl]amino}-6-[(8S)-3-cyanopyrrolo[1,2-b]pyridazin-7-yl]-N-[(2S)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, phosphorylated, signaling protein, inhibitor complex, immune system, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 139276.32

Authors

Ferrao, R.,Lansdon, E.B. (deposition date: 2025-02-11, release date: 2025-05-28)

Primary citation

Ammann, S.E.,Cottell, J.J.,Wright, N.E.,Warr, M.R.,Snyder, C.A.,Bacon, E.M.,Brizgys, G.,Chin, E.,Chou, C.,Conway, A.,Dick, R.A.,Ferrao, R.D.,Garrison, K.L.,Hammond, A.,Lansdon, E.B.,Link, J.O.,Mukherjee, P.K.,Murray, B.P.,Mwangi, J.,Ndukwe, M.S.,Park, G.Y.,Serone, A.P.,Suekawa-Pirrone, K.,Yang, Z.Y.,Zipfel, S.M.,Taylor, J.G.
Discovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4.
J.Med.Chem., 2025

PubMed Abstract: Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery of GS-5718 (edecesertib), a potent, selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor were efforts undertaken to improve the chemical series' profile after a significant hERG liability was encountered for an early compound. GS-5718 was safe and well-tolerated in IND-enabling preclinical animal toxicity studies, demonstrated efficacy in a mouse NZB lupus model, and additionally demonstrated human pharmacokinetic properties suitable for once-daily administration. Edecesertib is currently under clinical evaluation for the treatment of lupus.

PubMed: 40375634
DOI: 10.1021/acs.jmedchem.5c00463

Experimental method

X-RAY DIFFRACTION (2.14 Å)