Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S 
proteasome, is remarkably effective against multiple myeloma (MM) but not 
against solid tumors. Dose-limiting adverse effects from "on target" inhibition 
of the proteasome in normal cells and tissues appear to be a key obstacle. 
Achieving efficacy against solid tumors therefore is likely to require making 
the inhibitor more selective for tumor tissue over normal tissues. The simplest 
strategy that might provide such tissue specificity would be to employ a tumor 
specific protease to release an inhibitor from a larger, noninhibitory 
structure. However, such release would necessarily generate an inhibitor with a 
free N-terminal amino group, raising a key question: Can short peptide boronic 
acids with N-terminal amino groups have the requisite properties to serve as 
warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest 
plausible candidates for the task, can indeed be sufficiently potent, 
cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to 
serve in this capacity.