6X86

Crystal Structure of TNFalpha with indolinone compound 11

Summary for 6X86

• Entry DOI: 10.2210/pdb6x86/pdb
• Descriptor: Tumor necrosis factor, 3-[(6-{2-[(3R)-4-(hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-2,2-dimethyl-3-oxo-2,3-dihydro-1H-indol-1-yl)methyl]pyridine-2-carbonitrile (3 entities in total)
• Functional Keywords: trimer, inhibitor complex, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 106034.27

Authors

Longenecker, K.L.,Stoll, V.S. (deposition date: 2020-06-01, release date: 2021-01-13, Last modification date: 2024-10-16)

Primary citation

Dietrich, J.D.,Longenecker, K.L.,Wilson, N.S.,Goess, C.,Panchal, S.C.,Swann, S.L.,Petros, A.M.,Hobson, A.D.,Ihle, D.,Song, D.,Richardson, P.,Comess, K.M.,Cox, P.B.,Dombrowski, A.,Sarris, K.,Donnelly-Roberts, D.L.,Duignan, D.B.,Gomtsyan, A.,Jung, P.,Krueger, A.C.,Mathieu, S.,McClure, A.,Stoll, V.S.,Wetter, J.,Mankovich, J.A.,Hajduk, P.J.,Vasudevan, A.,Stoffel, R.H.,Sun, C.
Development of Orally Efficacious Allosteric Inhibitors of TNF alpha via Fragment-Based Drug Design.
J.Med.Chem., 64:417-429, 2021

PubMed Abstract: Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

PubMed: 33378180
DOI: 10.1021/acs.jmedchem.0c01280

Experimental method

X-RAY DIFFRACTION (2.93 Å)