Dipeptidyl boronic acids are suitable candidates for the design of “pro-soft” drugs because recent studies have proven that these acids undergo a pH-dependent cy - clization equilibrium, generating an inactive cyclic form under physiological conditions. Dipeptidyl boronic acids possess a wide range of potential targets, and the 26S proteasome appears to be one of the main targets. This multicatalytic complex is involved in intracellular protein turnover and is overexpressed in certain patho - logical conditions, such as malignancies, autoimmune diseases and neurodegenerative diseases. Bortezomib is the first-in-class derivative approved by the Food and Drug Administration for the treatment of hematologi - cal malignancies ( i.e. , relapsed and refractory multiple myeloma and mantle cell lymphoma) but is inactive against solid tumors due to an insufficient tissue distri - bution. The present study suggests a possible strategy for enhancing the in vivo performance of dipeptidyl boronic acids endowed with promising proteasome- inhibiting properties and their applicability as anticancer agents. In particular, dipeptidyl boronic acids might have a fruitful application as pro-soft drugs when an appropriate recognition motif serves as a substrate for a tumor-specific protease, generating the active form of the drug in situ and preventing systemic side effects after diffusion through cells and tissues.
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