A Novel Prodrug of a gamma-Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer

作者：Ii Hiromi; Yoshiya Taku; Nakata Susumu; Taniguchi Keiko; Hidaka Koushi; Tsuda Shugo; Mochizuki Masayoshi; Nishiuchi Yuji; Tsuda Yuko; Ito Kosei; Kageyama Susumu; Yoshiki Tatsuhiro^*

来源：ChemMedChem, 2018, 13(2): 155-163.

DOI：10.1002/cmdc.201700660

• antitumor agents
• membrane permeability
• prodrugs
• N-glutaryl-L-alanine
• gamma-glutamylcyclotransferase

gamma-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-L-alanine (GA), by structure optimization using temporary fluorophore-tagged prodrug candidates. The antiproliferative activity of pro-GA was demonstrated using GGCT-overexpressing NIH-3T3 cells and human cancer cells including MCF7, HL-60, and PC3 cells. By contrast, normal cells were not significantly affected by pro-GA treatment. Moreover, pro-GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT-overexpressing tumors.

• 出版日期2018-1-22