A central goal of the pharmaceutical and biotechnology industries is to identify small, stable, cell-permeable molecules capable of inhibiting the activity of cellular proteins that contribute to cancer. We propose a general method for developing inhibitors that exploits the unique characteristics of the ubiquitin-dependent proteolytic system of eukaryotic cells. The ultimate purpose of our research is to identify a cell-permeable molecule that binds to the substrate-docking site of a ubiquitin ligase. By covalently linking this molecule to other compounds that bind specific cellular proteins, we intend to develop a new class of drugs that can trigger the destruction of any protein in eukaryotic cells for which there exists a small, cell-permeable ligand. Our goal is to develop an experimental system to prove that this new concept for drug design is experimentally feasible. To this end, we have used an IkBa phosphopeptide that binds with high affinity to the substrate-docking domain of the ubiquitin ligase bTrCP. We have chemically linked this peptide to the fungal metabolite fumagillin, which binds specifically to the cellular enzyme methionine aminopeptidase-2 (MetAP-2). Our results indicate that the peptide–fumagillin chimera tethered the enzyme to bTrCP and targeted it for ubiquitination and degradation. We hope to expand this approach to develop new strategies to treat cancer.