A Targeted Covalently Activated Chemotherapy Strategy Synergistically Enhances Cytotoxicity of Ibrutinib and Selectivity of Doxorubicin to B-cell Lymphoma Cells.

To address the low cytotoxicity and drug resistance issues of targeted covalent inhibitor (TCI) ibrutinib and severe side effects of chemotherapeutics doxorubicin (DOX), we developed a novel targeted covalently activated chemotherapy strategy. We designed and synthesized a targeted covalently activated chemotherapy drug, Ibt-DOX, which features a targeting ligand of ibrutinib, a DOX, an electrophilic warhead α-methylated acrylamide (α-MAA) and a self-immolative linker p-hydroxybenzyl alcohol. Upon specifically binding to BTK, Ibt-DOX inhibits the BTK-mediated BCR signaling, meanwhile releases DOX and induces immunogenic cell death (ICD), ultimately resulting in not only significantly enhanced targeted B-cell lymphoma cells death compared with ibrutinib, but also reduces the toxic side effects of DOX on BTK- cells. Our work offers a novel strategy through leveraging the synergistic effect of targeted covalent inhibition and the high cytotoxicity of chemotherapy drug, which will inspire the development of new targeted covalent chemotherapeutics for different cancers treatment.