- Small-molecule inhibition of TNF-alpha.
Small-molecule inhibition of TNF-alpha.
Science (New York, N.Y.) (2005-11-15)
Molly M He, Annemarie Stroustrup Smith, Johan D Oslob, William M Flanagan, Andrew C Braisted, Adrian Whitty, Mark T Cancilla, Jun Wang, Alexey A Lugovskoy, Josh C Yoburn, Amy D Fung, Graham Farrington, John K Eldredge, Eric S Day, Leslie A Cruz, Teresa G Cachero, Stephan K Miller, Jessica E Friedman, Ingrid C Choong, Brian C Cunningham
PMID16284179
ABSTRACT
We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha 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-alpha subunits.
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