Legubicin a Tumor-Activated Prodrug for Breast Cancer Therapy

摘要

Legumain is a recently discovered and only known asparaginyl endopeptidase that is well conserved throughout the biologic kingdoms. We have demonstrated that legumain is highly and inappropriately expressed in 100% human breast cancer specimens as well as murine breast cancer models. We demonstrated that an inactive prototype doxorubicin derived prodrug incorporating a succinyl blocked substrate peptide removable by legumain was effectively activated and tumoricidal in human breast cancer models. We designated this prodrug legubicin. Legubicin is not cytotoxic until activated by legumain due to reduced ability to enter cells and blocked binding to DNA. These properties led to increased tumor exposure and much reduced drug accumulation in normal tissues when administered in vivo. It has markedly reduced cardiac and myelosuppressive toxicities compare to doxorubicin. In this grant application we propose to further develop this prodrug strategy as a potential treatment for breast cancer.