Small Molecule Inhibits Tnf-α

A small-molecule inhibitor of tumor necrosis factor α (TNF-α), a protein involved in diseases such as rheumatoid arthritis, has been identified. Commercially available inhibitors, such as Enbrel and Remicade, are biological agents. A collaborative team led by Brian C. Cunningham of Sunesis Pharmaceuticals reports that a small molecule (shown) composed of trifluoromethylphenyl indole and dimethyl chromone moieties linked by a dimethylamine spacer inhibits binding of TNF-α to its receptor. They find median inhibitory concentrations of 22 µM in biochemical assays and 4.6 µM in cell-based assays (Science 2005, 310, 1022). An X-ray crystal structure of the compound with TNF-α reveals that the inhibitor displaces one of the three subunits in the protein and forms a complex with a dimer of TNF-α subunits. The results should help with the design of assays for identifying other small-molecule inhibitors that inactivate multimeric proteins by causing them to dissociate, the authors say.