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Journal of Clinical & Experimental Pathology | ISSN: 2161-0681 | Volume 8
Breast Pathology and Cancer Diagnosis
6th World Congress and Expo on
July 25-26, 2018 | Vancouver, Canada
Medicinal Chemistry and Rational Drugs
20 th International Conference on
&
A Novel prodrug of glutamylcyclotransferase inhibitor has anti-proliferative activity in vitro and anti-
cancer activity in vivo
Hiromi Ii1, Taku Yoshiya2,Susumu Nakata1, Keiko Taniguchi1, Koushi Hidaka3, Shugo Tsuda2, Masayoshi Mochizuki2, Yuji Nishiuchi2, Yuko Tsuda3, Kosei
Ito4, Susumu Kageyama5 and Tatsuhiro Yoshiki1,4
1Kyoto Pharmaceutical University, Japan
2Peptide Institute Inc., Japan
3Kobe Gakuin University, Japan
4Nagasaki University, Japan
5Shiga University of Medical Science, Japan
C 7 or f24 was discovered as a highly expressed protein in bladder cancers by a proteomic analysis and later identified
as the α-glutamylcyclotransferase (GGCT). The silencing of GGCT using siRNA inhibited cancer cell proliferation and
tumor growth in mice inoculated with cancer cells. However, the relationship between GGCT enzymatic activity and these
phenotypes remained unknown.Therefore, we tried to identify a potent GGCT inhibitor and investigated its anti-cancer activity
in vitro and in a xenograft mouse model. We performed a screening of GGCT inhibitors from 41 candidate compounds, and
identified N-glutaryl-L-Ala (GA) that showed the highest inhibitory activity. Next, we used a NBD fluorochrome-tagged GA,
Nα-glutaryl-L-Lys (NBD), to evaluate cell permeability. However, no signal derived from NBD was observed inside cells. In
order to improve its permeability, we generated a less polar prodrug “Nα-methoxyglutaryl-L-Lys(NBD)-OCH2OCOCH3 (Me-
gKFA-AM)” where carboxylates in the structure of the parent inhibitor were substituted by alkyl esters. As had been expected,
Me-gKFA-AM was successfully internalized into the cells and conversion of the prodrug into the parent drug in MCF-7 breast
cancer cells was confirmed by HPLC. We demonstrated anti-proliferative activity of the methyl-acetoxymethyl ester prodrug of
GA (pro-GA) in human MCF7, HL-60, and PC3 cancer cells in vitro. Moreover, pro-GA administration exhibited anti-cancer
effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the pro-GA
may be promising as a lead compound to inhibit GGCT activity for the novel cancer therapeutic strategy.
Biography
Hiromi Ii has completed her PhD at Kyoto Pharmaceutical University in 2008 and postdoctoral studies at University of Washington. She is an assistant professor of
the Department of Clinical Oncology, Kyoto Pharmaceutical University.
Hiromi Ii et al., J Clin Exp Pathol 2018, Volume 8
DOI: 10.4172/2161-0681-C3-051