Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy

•Synthesis of the first glucuronide prodrug of the potent monomethylauristatin E.•Efficient release of the drug upon enzymatic activation.•Subnanomolar cytotoxic activity against several cancer cell lines.•Significant cytotoxic effect on primary cultures of patients with lung cancer.•Significant antitumor effect without overt toxicity in vivo.

We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of β-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.

Graphical abstractThe glucuronide prodrug 1 of the potent monomethylauristatin E (MMAE) was synthesized and evaluated as a potential selective antitumor agent for the treatment of solid tumors.Figure optionsDownload full-size imageDownload as PowerPoint slide