Immunoproteasome Inhibitor–Doxorubicin Conjugates Target Multiple Myeloma Cells and Release Doxorubicin upon Low-Dose Photon Irradiation

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.