Identification of a selectivity determinant for inhibition of tumor necrosis factor-α converting enzyme by comparative modeling

Inhibition of tumor necrosis factor-alpha converting enzyme (TACE) is a widespread objective in the search for disease modifying agents to combat rheumatoid arthritis and other autoimmune diseases. Until recently, most of the inhibitors in the literature have shown concomitant activity against the related matrix metalloproteinases (MMPs), producing undesired side effects. Here we describe the successful search for a TACE selectivity mechanism. We built a homology model based on the crystal structure of the related snake venom protein atrolysin. Comparison of the model with crystal structures of MMPs suggested a uniquely shaped S1' pocket that might be exploited for selectivity. A novel gamma-lactam scaffold [1] was used to explore the activity profile of P1' sidechains, resulting in highly selective compounds consistent with this hypothesis. Transferability of the hypothesis was then demonstrated with five other distinct scaffolds.