Design and synthesis of alpha-ketoamides as cathepsin S inhibitors with potential applications against tumor invasion and angiogenesis.

A series of small molecules bearing an alpha-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC(50) < 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of alpha-ketoamide therapy for preventing or delaying cancer spread.