期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 16, 页码 7250-7253出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b11969
关键词
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资金
- Nederland Genomics Initiative (Zenith) - European Research Council [ERC-2014-StG-639005]
Proteasome inhibitors are established therapeutic agents for the treatment of hematological cancers, as are anthracyclines such as doxorubicin. We here present a new drug targeting approach that combines both drug classes into a single molecule. Doxorubicin was conjugated to an immunoproteasome-selective inhibitor via light-cleavable linkers, yielding peptide epoxyketone-doxorubicin prodrugs that remained selective and active toward immunoproteasomes. Upon cellular uptake and immunoproteasome inhibition, doxorubicin is released from the immunoproteasome inhibitor through photoirradiation. Multiple myeloma cells in this way take a double hit: immunoproteasome inhibition and doxorubicin-induced toxicity. Our strategy, which entails targeting of a cytotoxic agent, through a covalent enzyme inhibitor that is detrimental to tumor tissue in its own right, may find use in the search for improved anticancer drugs.
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