Asubio Pharma Co., Ltd., 6-4-3, Minatojima-minamimachi, Chuou-ku, Kobe, Japan.
J Pharmacol Sci. 2019 Jul;140(3):242-247. doi: 10.1016/j.jphs.2019.07.009. Epub 2019 Aug 3.
xCT, 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.
xCT 是一种众所周知的胱氨酸转运体，据报道它参与了各种细胞的增殖，如癌细胞、免疫细胞和成纤维细胞。xCT 抑制剂有望成为治疗癌症或免疫疾病的有前途的药物。然而，很少有研究报道 xCT 抑制剂能改善体内疾病的进展。为了在体内发明有效的 xCT 抑制剂，我们建立了一种新的体内模型来评估 xCT 抑制的疗效。dl-炔丙基甘氨酸（PPG）被腹腔内给药给野生型 C57BL/6J 小鼠。用 LC-MS/MS 测量胸腺和脾脏中另一种 xCT 底物胱硫醚的浓度。PPG 以剂量和时间依赖的方式增加了胸腺和脾脏中的胱硫醚含量。在 PPG 给药 7 小时后，明显显示出代表性的 xCT 抑制剂 erastin 的疗效。我们合成了一种新的化合物 A，它在体外和体内对 xCT 的抑制作用比 erastin 强得多。我们建立了一种 PPG 诱导的胱硫醚积累的小鼠模型，用于评估体内的 xCT 抑制作用。通过使用这种模型，我们发现化合物 A 在体内的效果比 erastin 约强 15 倍。
