Proteasomes

Rechsteiner, Martin

doi:10.1002/3527600906.mcb.200400063

Cited by 1 publication

(1 citation statement)

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“…Proteasome inhibition results in the buildup of misfolded and damaged intracellular proteins, leading to the disruption of multiple cellular signaling pathways and ultimately cell death. − Multiple myeloma cells seem to be especially sensitive to proteasome inhibition, quite likely because of their overproduction of protein and high protein turnover, resulting in greater need for proteasomal degradation and clearance. ,,,,,,, Nevertheless, all cells, both normal and malignant, require a functioning proteasome. Different types of cells exhibit differences in sensitivity to proteasome inhibition, but proteasome inhibition will, at some level and duration, be lethal to essentially any cell.…”

Section: Introductionmentioning

confidence: 99%

Chemical and Biological Evaluation of Dipeptidyl Boronic Acid Proteasome Inhibitors for Use in Prodrugs and Pro-Soft Drugs Targeting Solid Tumors

Milo

Lai

et al. 2011

J. Med. Chem.

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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.

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