Small-Molecule Inhibition of TNF-α

• DOI: 10.1126/science.1116304
• Publication Date: 2005-11-10T22:33:25Z
• Authors: Molly M. He; Annemarie Stroust...; 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
• Keywords: Trimer

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations 22 4.6 micromolar, respectively. Formation an intermediate complex between the intact trimer results 600-fold accelerated dissociation rate leads to dissociation. A structure solved by x-ray crystallography reveals single molecule displaces form dimer subunits.