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

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JOURNAL OF MECHANICAL ENGINEERING > 2022 > Accepted Manuscript

Fangfang Lai, Ming Ji, Lei Huang, Yunchen Wang, Nina Xue, Tingting Du, Kai Dong, Xiaoqing Yao, Jing Jin, Zhiqiang Feng, Xiaoguang Chen. YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.031

Citation:

Fangfang Lai, Ming Ji, Lei Huang, Yunchen Wang, Nina Xue, Tingting Du, Kai Dong, Xiaoqing Yao, Jing Jin, Zhiqiang Feng, Xiaoguang Chen. YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.031

Citation:

Fangfang Lai, Ming Ji, Lei Huang, Yunchen Wang, Nina Xue, Tingting Du, Kai Dong, Xiaoqing Yao, Jing Jin, Zhiqiang Feng, Xiaoguang Chen. YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.031

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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

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:

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).

Received Date: 29 Oct 2021
Rev Recd Date: 13 Dec 2021
Accepted Date: 17 Feb 2022

Available Online: 17 Mar 2023

Abstract

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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References(33)

References

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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

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