Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges
The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised antic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383456/full |
| _version_ | 1797215908427464704 |
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| author | Sadique A. Javed Asim Najmi Waquar Ahsan Khalid Zoghebi |
| author_facet | Sadique A. Javed Asim Najmi Waquar Ahsan Khalid Zoghebi |
| author_sort | Sadique A. Javed |
| collection | DOAJ |
| description | The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition. |
| first_indexed | 2024-04-24T11:37:32Z |
| format | Article |
| id | doaj.art-ac3a6bc64747497c868c5f1f57189441 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T11:37:32Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ac3a6bc64747497c868c5f1f571894412024-04-10T04:35:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13834561383456Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challengesSadique A. JavedAsim NajmiWaquar AhsanKhalid ZoghebiThe programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383456/fullcancer immunotherapyimmune checkpointmonoclonal antibodiessmall molecule inhibitorsPD-1/PD-L-1 |
| spellingShingle | Sadique A. Javed Asim Najmi Waquar Ahsan Khalid Zoghebi Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges Frontiers in Immunology cancer immunotherapy immune checkpoint monoclonal antibodies small molecule inhibitors PD-1/PD-L-1 |
| title | Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges |
| title_full | Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges |
| title_fullStr | Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges |
| title_full_unstemmed | Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges |
| title_short | Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges |
| title_sort | targeting pd 1 pd l 1 immune checkpoint inhibition for cancer immunotherapy success and challenges |
| topic | cancer immunotherapy immune checkpoint monoclonal antibodies small molecule inhibitors PD-1/PD-L-1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383456/full |
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