Small-Molecule Inhibition of TNF-α

Autor: Graham K. Farrington, Jessica E. Friedman, Joshua C. Yoburn, Alexey Lugovskoy, William Michael Flanagan, Stephan K. Miller, Brian C. Cunningham, Amy D. Fung, Adrian Whitty, Molly M. He, Jun Wang, Annemarie Stroustrup Smith, Mark T. Cancilla, John Eldredge, Leslie A. Cruz, Johan D. Oslob, Teresa G. Cachero, Andrew C. Braisted, Eric S. Day, Ingrid C. Choong
Rok vydání: 2005
Předmět:
Zdroj: Science. 310:1022-1025
ISSN: 1095-9203
0036-8075
Popis: We have identified a small-molecule inhibitor of tumor necrosis factor α (TNF-α) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-α activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-α subunits.
Databáze: OpenAIRE
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