9OK6

Crystal structure of TNF alpha in complex with compound 19

This is a non-PDB format compatible entry.

Summary for 9OK6

• Entry DOI: 10.2210/pdb9ok6/pdb
• Related: 9OJO 9OJS 9OJY
• Descriptor: Tumor necrosis factor, (4S,8aR)-7-{5-[(6R,13R,14S)-5,14-dihydro-7H-6,14-methanopyrido[3',2':4,5]imidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}hexahydroimidazo[1,5-a]pyrazin-3(2H)-one (3 entities in total)
• Functional Keywords: tumor necrosis factor alpha, structure-based drug design, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 105970.20

Authors

Judge, R.A.,Longenecker, K.L.,Bian, Z. (deposition date: 2025-05-09, release date: 2025-07-23, Last modification date: 2025-08-27)

Primary citation

Bian, Z.,Schmidt, R.G.,Wilson, N.S.,Duignan, D.B.,Breinlinger, E.,Dombrowski, A.W.,Erdman, P.,Foley, C.M.,Friedman, M.,Gfesser, G.A.,Goess, C.A.,Gomtsyan, A.,Judge, R.A.,Kikuchi, R.,Koshman, Y.,Liu, X.,Longenecker, K.L.,McClure, A.,Sippy, K.,Wetter, J.M.,Stoffel, R.,Vasudevan, A.
Discovery of Orally Efficacious Bridged Piperazines as smTNF Modulators.
J.Med.Chem., 68:14357-14383, 2025

PubMed Abstract: Tumor necrosis factor α (TNFα) plays a critical role in inflammatory and autoimmune diseases. While biologic drugs have improved patient outcomes in conditions like rheumatoid arthritis by disrupting TNFα signaling, small molecule targeting has been challenging due to the strong TNF-receptor binding and difficulty in disrupting the TNF trimer. This research presents small molecule TNFα inhibitors with a novel bridged-piperazine core, developed through molecular dynamics simulation and scaffold hopping. The initial hit was optimized using structure-based design, leading to the discovery of a lead molecule with similar potency to the prototype but enhanced physicochemical properties. This lead demonstrated oral efficacy in a mouse glucose-6-phosphate isomerase-induced paw swelling model, comparable to the effects of a TNFα antibody. The estimated effective human dose is 200 mg once daily, highlighting the potential for clinical development of these compounds.

PubMed: 40632677
DOI: 10.1021/acs.jmedchem.5c00323

Experimental method

X-RAY DIFFRACTION (2.776 Å)