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Novel mouse model for evaluating in vivo efficacy of xCT inhibitor
Ryosuke Yoshioka1, Yusuke Fujieda1, Yamato Suzuki1
1Asubio Pharma Co., Ltd., 6-4-3, Minatojima-minamimachi, Chuou-ku, Kobe, Japan.
Abstract:
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.
Insights
Researchers developed a new mouse model to test xCT inhibitors, crucial for treating cancer and immune diseases. This model helped discover Compound A, a potent xCT inhibitor significantly more effective in vivo than existing drugs.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- The cystine transporter xCT is implicated in the proliferation of cancer cells, immune cells, and fibroblasts.
- xCT inhibitors show promise for treating cancer and immune diseases, but in vivo efficacy data is limited.
Purpose of the Study:
- To establish a novel in vivo model for assessing the efficacy of xCT inhibition.
- To discover potent xCT inhibitors with improved in vivo activity.
Main Methods:
- Administration of dl-propargylglycine (PPG) to wild-type C57BL/6J mice to induce cystathionine accumulation.
- Quantification of cystathionine levels in thymus and spleen using LC-MS/MS.
- In vitro and in vivo evaluation of a newly synthesized compound, Compound A, compared to erastin.
Main Results:
- PPG administration led to dose- and time-dependent increases in cystathionine in the thymus and spleen.
- The efficacy of erastin as an xCT inhibitor was confirmed in vivo at 7 hours post-PPG administration.
- Compound A demonstrated significantly higher in vitro and in vivo xCT inhibitory effects compared to erastin, showing approximately 15-fold greater efficacy in vivo.
Conclusions:
- A validated mouse model for assessing in vivo xCT inhibition was successfully established.
- Compound A represents a highly potent xCT inhibitor with superior in vivo efficacy, warranting further investigation for therapeutic applications in cancer and immune diseases.
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