9PSU

IRAK4 in Complex with Compound 12

This is a non-PDB format compatible entry.

Summary for 9PSU

• Entry DOI: 10.2210/pdb9psu/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, N-[(1R,5S,8R)-3-(5-{(6P)-6-[(8S)-3-cyanopyrrolo[1,2-b]pyridazin-7-yl]-4-[(propan-2-yl)amino]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]acetamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, phosphorylated, signaling protein, inhibitor complex, immune system, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 138940.92

Authors

Ferrao, R. (deposition date: 2025-07-26, release date: 2026-01-28)

Primary citation

Ammann, S.E.,Brizgys, G.,Ferrao, R.D.,Wright, N.E.,Mukherjee, P.K.,Bacon, E.M.,Chin, E.,Chou, C.,Cottell, J.J.,Hammond, A.,Ndukwe, M.S.,Park, G.Y.,Shatskikh, M.E.,Suekawa-Pirrone, K.,Warr, M.R.,Yang, Z.Y.,Zipfel, S.M.,Taylor, J.G.
Examination of Noncanonical Kinase Hinge Binders Leads to Thiadiazoles as Potent IRAK4 Inhibitors.
Acs Med.Chem.Lett., 17:175-182, 2026

PubMed Abstract: A hallmark of most known small-molecule orthosteric kinase inhibitors is hydrogen-bonding to the hinge-region of the kinase to mimic the hinge interaction of adenine. Herein we report our studies on deviation from canonical hinge-binders in the context of IRAK4 inhibitors. Small-molecule inhibitors of IRAK4 have generated interest as potential treatments for inflammatory diseases. Notably, in our discovery efforts we identified pyridinyl-thiadiazoles as noncanonical hinge-binders. X-ray structural evidence supports that the thiadiazole moiety engages in a rare intermolecular noncovalent sulfur-oxygen interaction. This thiadiazole series, exemplified by compounds and , has shown promise for potent, selective, orally bioavailable IRAK4 inhibitors.

PubMed: 41531974
DOI: 10.1021/acsmedchemlett.5c00602

Experimental method

X-RAY DIFFRACTION (2.43 Å)