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

Thibaut Legigan (1) , Jonathan Clarhaut (2) , Brigitte Renoux (1) , Isabelle Tranoy-Opalinski (1) , Arnaud Monvoisin (3) , Christophe Jayle (4) , Jérôme Alsarraf (1) , Mikaël Thomas (1) , Sébastien Papot (1)

1 IC2MP [Poitiers] - Institut de chimie des milieux et matériaux de Poitiers [UMR 7285]
2 INSERM - CHU de Poitiers - INSERM CIC 0802
3 IPBC - Institut de physiologie et biologie cellulaires
4 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital

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.

Mots clés: Cancer; Chemotherapy; Glucuronide; Prodrug; Tumor targeting

Domaines: Sciences du Vivant [q-bio]

Thibaut Legigan, Jonathan Clarhaut, Brigitte Renoux, Isabelle Tranoy-Opalinski, Arnaud Monvoisin, et al.. Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy. European Journal of Medicinal Chemistry, 2013, 67, pp.75-80. ⟨10.1016/j.ejmech.2013.06.037⟩. ⟨hal-04033523⟩