Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents
Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383522001770 |
| _version_ | 1828271501229424640 |
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| author | Chengliang Sun Yao Cheng Xiaojia Liu Gefei Wang Wenjian Min Xiao Wang Kai Yuan Yi Hou Jiaxing Li Haolin Zhang Haojie Dong Liping Wang Chenguang Lou Yanze Sun Xinmiao Yu Hongbin Deng Yibei Xiao Peng Yang |
| author_facet | Chengliang Sun Yao Cheng Xiaojia Liu Gefei Wang Wenjian Min Xiao Wang Kai Yuan Yi Hou Jiaxing Li Haolin Zhang Haojie Dong Liping Wang Chenguang Lou Yanze Sun Xinmiao Yu Hongbin Deng Yibei Xiao Peng Yang |
| author_sort | Chengliang Sun |
| collection | DOAJ |
| description | Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells. |
| first_indexed | 2024-04-13T05:54:21Z |
| format | Article |
| id | doaj.art-a69639855c5f49b5a96f30c02c1d0a7c |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-13T05:54:21Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-a69639855c5f49b5a96f30c02c1d0a7c2022-12-22T02:59:40ZengElsevierActa Pharmaceutica Sinica B2211-38352022-12-01121244464457Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agentsChengliang Sun0Yao Cheng1Xiaojia Liu2Gefei Wang3Wenjian Min4Xiao Wang5Kai Yuan6Yi Hou7Jiaxing Li8Haolin Zhang9Haojie Dong10Liping Wang11Chenguang Lou12Yanze Sun13Xinmiao Yu14Hongbin Deng15Yibei Xiao16Peng Yang17State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaBeijing Institute of Clinical Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, DenmarkState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Corresponding authors.State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Corresponding authors.State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Corresponding authors.Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.http://www.sciencedirect.com/science/article/pii/S2211383522001770PD-1/PD-L1Small-molecule inhibitorImmunotherapyCo-crystal structure |
| spellingShingle | Chengliang Sun Yao Cheng Xiaojia Liu Gefei Wang Wenjian Min Xiao Wang Kai Yuan Yi Hou Jiaxing Li Haolin Zhang Haojie Dong Liping Wang Chenguang Lou Yanze Sun Xinmiao Yu Hongbin Deng Yibei Xiao Peng Yang Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents Acta Pharmaceutica Sinica B PD-1/PD-L1 Small-molecule inhibitor Immunotherapy Co-crystal structure |
| title | Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| title_full | Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| title_fullStr | Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| title_full_unstemmed | Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| title_short | Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| title_sort | novel phthalimides regulating pd 1 pd l1 interaction as potential immunotherapy agents |
| topic | PD-1/PD-L1 Small-molecule inhibitor Immunotherapy Co-crystal structure |
| url | http://www.sciencedirect.com/science/article/pii/S2211383522001770 |
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