Strategies for developing PD-1 inhibitors and future directions.
Biochem Pharmacol
; 202: 115113, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35640711
ABSTRACT
PD-L1/PD-1 signaling pathway is unarguably the hottest target for developing therapeutics against various types of cancers. With elucidation of crystal structure of PD-1/PD-L1, inhibitors targeting PD-1, PD-L1 or protein-protein interaction between them have been reported. Identification of transcription factors responsible for transcription of mRNA encoding PD-1 and PD-L1 promoted developing inhibitors to downregulate expression of either gene. Elucidation of PD-1 signaling pathway broadened strategies for drug design, for example to interfere recruitment of SHP2 by PD-1. Post-transcription modification (PTM) of phosphorylation, glycosylation, ubiquination and palmitoylation have been reported to modulate the function or homeostasis of proteins of PD-1 or PD-L1. Drugs targeting elements responsible for these PTM have been reported to enhance T cell mediated immunity. Moreover, cleverly designed protein-degrading reagents, either macromolecules or small chemicals (PROTACs) have been tried against PD-1 or PD-L1. In this review we will talk about crystal structure of PD-1/PD-L1, PD-1 signaling pathway, and physiological and pathological roles played by PD-1. Particular attention is paid on strategies for developing drugs targeting PD-1 pathways. For future directions of strategies for developing PD-1/PD-L1 inhibitors, we suggest two realistic fields bi-functional or multi-functional small molecules; nano-material to deliver siRNAs. With recent identification of many more checkpoints in T cells through genome-wide screening and harnessing the power of nano-materials to pack multiple siRNAs, tumor microenvironment T cell specific mano-materials containing siRNAs against PD-1 and other checkpoints simultaneously could be of particular interest to industry.
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MEDLINE
Assunto principal:
Antígeno B7-H1
/
Neoplasias
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article