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: 0303 health sciences; 03 medical and health sciences; 3. Good health

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.