YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

Fangfang Lai; Ming Ji; Lei Huang; Yunchen Wang; Nina Xue; Tingting Du; Kai Dong; Xiaoqing Yao; Jing Jin; Zhiqiang Feng; Xiaoguang Chen

doi:10.1016/j.apsb.2022.02.031

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

doi: 10.1016/j.apsb.2022.02.031

a. Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
b. Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
c. Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 300170, China

基金项目:

This work was supported by the National Natural Science Foundation of China (No. 81872923), the CAMS Innovation Fund for Medical Sciences (2016-I2M-3-008, China) and The Drug Innovation Major Project (No. 2018ZX09711001-003, China).

详细信息

通讯作者:
Jing Jin,E-mail:rebeccagold@imm.ac.cn

Zhiqiang Feng,E-mail:fengzhq@imm.ac.cn

Xiaoguang Chen,E-mail:chxg@imm.ac.cn

中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383522000971/pdf?md5=238d460a7c4a4890c736f4eab1f38d53&pid=1-s2.0-S2211383522000971-main.pdf
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出版历程
- 收稿日期: 2021-10-29
- 修回日期: 2021-12-13
- 录用日期: 2022-02-17
- 网络出版日期: 2023-03-17

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

a. Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
b. Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
c. Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 300170, China

Funds:

摘要

摘要: PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.
- PD-L1 /
- Small molecular inhibitor /
- Prodrug /
- Immune checkpoints /
- Cancer immunotherapy
Abstract: PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.
- PD-L1 /
- Small molecular inhibitor /
- Prodrug /
- Immune checkpoints /
- Cancer immunotherapy

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参考文献(33)

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YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

doi: 10.1016/j.apsb.2022.02.031

通讯作者:
Jing Jin,E-mail:rebeccagold@imm.ac.cn

Zhiqiang Feng,E-mail:fengzhq@imm.ac.cn

Xiaoguang Chen,E-mail:chxg@imm.ac.cn

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YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

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YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

doi: 10.1016/j.apsb.2022.02.031

通讯作者: Jing Jin,E-mail:rebeccagold@imm.ac.cn Zhiqiang Feng,E-mail:fengzhq@imm.ac.cn Xiaoguang Chen,E-mail:chxg@imm.ac.cn

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出版历程

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

计量

出版历程

目录

通讯作者:
Jing Jin,E-mail:rebeccagold@imm.ac.cn

Zhiqiang Feng,E-mail:fengzhq@imm.ac.cn

Xiaoguang Chen,E-mail:chxg@imm.ac.cn