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...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Book |
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Elsevier,
2022-12-01T00:00:00Z.
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| 042 | |a dc | ||
| 100 | 1 | 0 | |a Chengliang Sun |e author |
| 700 | 1 | 0 | |a Yao Cheng |e author |
| 700 | 1 | 0 | |a Xiaojia Liu |e author |
| 700 | 1 | 0 | |a Gefei Wang |e author |
| 700 | 1 | 0 | |a Wenjian Min |e author |
| 700 | 1 | 0 | |a Xiao Wang |e author |
| 700 | 1 | 0 | |a Kai Yuan |e author |
| 700 | 1 | 0 | |a Yi Hou |e author |
| 700 | 1 | 0 | |a Jiaxing Li |e author |
| 700 | 1 | 0 | |a Haolin Zhang |e author |
| 700 | 1 | 0 | |a Haojie Dong |e author |
| 700 | 1 | 0 | |a Liping Wang |e author |
| 700 | 1 | 0 | |a Chenguang Lou |e author |
| 700 | 1 | 0 | |a Yanze Sun |e author |
| 700 | 1 | 0 | |a Xinmiao Yu |e author |
| 700 | 1 | 0 | |a Hongbin Deng |e author |
| 700 | 1 | 0 | |a Yibei Xiao |e author |
| 700 | 1 | 0 | |a Peng Yang |e author |
| 245 | 0 | 0 | |a Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents |
| 260 | |b Elsevier, |c 2022-12-01T00:00:00Z. | ||
| 500 | |a 2211-3835 | ||
| 500 | |a 10.1016/j.apsb.2022.04.007 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a PD-1/PD-L1 | ||
| 690 | |a Small-molecule inhibitor | ||
| 690 | |a Immunotherapy | ||
| 690 | |a Co-crystal structure | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Acta Pharmaceutica Sinica B, Vol 12, Iss 12, Pp 4446-4457 (2022) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2211383522001770 | |
| 787 | 0 | |n https://doaj.org/toc/2211-3835 | |
| 856 | 4 | 1 | |u https://doaj.org/article/a69639855c5f49b5a96f30c02c1d0a7c |z Connect to this object online. |