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Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts
Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-lif...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630621/ https://www.ncbi.nlm.nih.gov/pubmed/34858943 http://dx.doi.org/10.3389/fchem.2021.766107 |
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author | Suzuki, Yoshihide Ichinohe, Keisuke Sugawara, Akihiro Kida, Shinya Murase, Shinya Zhang, Jing Yamada, Osamu Hattori, Toshio Oshima, Yoshiteru Kikuchi, Haruhisa |
author_facet | Suzuki, Yoshihide Ichinohe, Keisuke Sugawara, Akihiro Kida, Shinya Murase, Shinya Zhang, Jing Yamada, Osamu Hattori, Toshio Oshima, Yoshiteru Kikuchi, Haruhisa |
author_sort | Suzuki, Yoshihide |
collection | PubMed |
description | Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-life, and low manufacturing costs, and the possibility of oral administration. Thus, it is imperative to develop small-molecule immune checkpoint inhibitors. Previously, we have screened a library of synthetic indole-alkaloid-type compounds, which are produced by diversity-enhanced extracts of Japanese cornelian cherry, and reported that an unnatural pentacyclic compound inhibits CTLA-4 gene expression. In this study, immune checkpoint inhibitors with increased potency were developed by introducing substituents and conversion of functional groups based on the unnatural pentacyclic compound. The developed compounds suppressed not only CTLA-4 and PD-L1 gene expression but also protein expression on the cell surface. Their efficacy was not as potent as that of the existing small-molecule immune checkpoint inhibitors, but, to the best of our knowledge, the developed compounds are the first reported dual small-molecule inhibitors of CTLA-4 and PD-L1. |
format | Online Article Text |
id | pubmed-8630621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86306212021-12-01 Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts Suzuki, Yoshihide Ichinohe, Keisuke Sugawara, Akihiro Kida, Shinya Murase, Shinya Zhang, Jing Yamada, Osamu Hattori, Toshio Oshima, Yoshiteru Kikuchi, Haruhisa Front Chem Chemistry Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-life, and low manufacturing costs, and the possibility of oral administration. Thus, it is imperative to develop small-molecule immune checkpoint inhibitors. Previously, we have screened a library of synthetic indole-alkaloid-type compounds, which are produced by diversity-enhanced extracts of Japanese cornelian cherry, and reported that an unnatural pentacyclic compound inhibits CTLA-4 gene expression. In this study, immune checkpoint inhibitors with increased potency were developed by introducing substituents and conversion of functional groups based on the unnatural pentacyclic compound. The developed compounds suppressed not only CTLA-4 and PD-L1 gene expression but also protein expression on the cell surface. Their efficacy was not as potent as that of the existing small-molecule immune checkpoint inhibitors, but, to the best of our knowledge, the developed compounds are the first reported dual small-molecule inhibitors of CTLA-4 and PD-L1. Frontiers Media S.A. 2021-11-08 /pmc/articles/PMC8630621/ /pubmed/34858943 http://dx.doi.org/10.3389/fchem.2021.766107 Text en Copyright © 2021 Suzuki, Ichinohe, Sugawara, Kida, Murase, Zhang, Yamada, Hattori, Oshima and Kikuchi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Suzuki, Yoshihide Ichinohe, Keisuke Sugawara, Akihiro Kida, Shinya Murase, Shinya Zhang, Jing Yamada, Osamu Hattori, Toshio Oshima, Yoshiteru Kikuchi, Haruhisa Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title | Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title_full | Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title_fullStr | Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title_full_unstemmed | Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title_short | Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts |
title_sort | development of indole alkaloid-type dual immune checkpoint inhibitors against ctla-4 and pd-l1 based on diversity-enhanced extracts |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630621/ https://www.ncbi.nlm.nih.gov/pubmed/34858943 http://dx.doi.org/10.3389/fchem.2021.766107 |
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