Novel mouse model for evaluating in vivo efficacy of xCT inhibitor

Publication date: Available online 3 August 2019Source: Journal of Pharmacological SciencesAuthor(s): Ryosuke Yoshioka, Yusuke Fujieda, Yamato Suzuki, Osamu Kanno, Asako Nagahira, Tomohiro Honda, Masao Murakawa, Hiroshi YukiuraAbstractxCT, a well-known cystine transporter, is reported to be involved in the proliferation of various cells, such as cancer cells, immune cells, and fibroblasts. xCT inhibitor is expected to be a promising drug for cancer or immune diseases. However, there are little studies reporting that xCT inhibitors improve disease progression in vivo. To invent potent xCT inhibitors in vivo, we established a new in vivo model for assessing efficacy of xCT inhibition.DL-propargylglycine (PPG) was administered intraperitoneally to wild-type C57BL/6J mice. Concentration of cystathionine, another substrate of xCT, in the thymus and spleen was measured by LC-MS/MS.PPG increased cystathionine amounts in the thymus and spleen in a dose- and time-dependent manner. At 7 h after PPG administration, the efficacy of erastin, a representative xCT inhibitor, was clearly shown. We synthesized a new compound, Compound A, which had much higher inhibitory effect on xCT than erastin both in vitro and in vivo.We established a mouse model of PPG-induced cystathionine accumulation for assessing xCT inhibition in vivo. By using this model, we discovered that Compound A was approximately 15 times more effective in vivo than erastin.
Source: Journal of Pharmacological Sciences - Category: Drugs & Pharmacology Source Type: research