A β‐Glucuronidase‐Responsive Albumin‐Binding Prodrug of a Potent Focal Adhesion Kinase Inhibitor for Targeted Cancer Therapy

Focal adhesion kinase (FAK) has emerged as a promising therapeutic target for cancer owing to its key roles in the development and aggressiveness of tumor malignancy. However, exploring the clinical translation of FAK inhibitors has been recently hindered by their lack of selectivity and specificity for cancer cells. In this study, the synthesis and biological evaluation of a trimeric β‐glucuronidase‐responsive albumin‐binding prodrug programmed for the selective delivery of a potent FAK inhibitor within solid tumors are reported. When activated by β‐glucuronidase, a glycosidase overexpressed in the microenvironment of numerous tumors, this prodrug induces a remarkable inhibition of breast cancer cell (MDA‐MB‐231) growth with an IC 50 value of 0.63 ± 0.02 μM. Furthermore, mechanistic studies show that upon enzymatic activation, the prodrug delays cell cycle progression by arresting cells in the G2/M phase. These results indicate that our delivery strategy may be applied as a promising new FAK‐targeted therapy for cancer.