YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer.
10.1016/j.apsb.2022.02.031
- Author:
Fangfang LAI
1
;
Ming JI
1
;
Lei HUANG
1
;
Yunchen WANG
1
;
Nina XUE
1
;
Tingting DU
1
;
Kai DONG
2
;
Xiaoqing YAO
2
;
Jing JIN
1
;
Zhiqiang FENG
3
;
Xiaoguang CHEN
1
Author Information
1. 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.
2. Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 300170, China.
3. Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
Cancer immunotherapy;
Immune checkpoints;
PD-L1;
Prodrug;
Small molecular inhibitor
- From:
Acta Pharmaceutica Sinica B
2022;12(6):2845-2858
- CountryChina
- Language:English
-
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.
