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...

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Autores principales:	Yoshihide Suzuki, Keisuke Ichinohe, Akihiro Sugawara, Shinya Kida, Shinya Murase, Jing Zhang, Osamu Yamada, Toshio Hattori, Yoshiteru Oshima, Haruhisa Kikuchi
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	immune checkpoint inhibitors natural products indole PD-L1 CTLA-4 diversity-enhanced extracts Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/5446e2a977fb434dabf63311a85d4f08
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spelling	oai:doaj.org-article:5446e2a977fb434dabf63311a85d4f082021-11-08T07:27:53ZDevelopment of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts2296-264610.3389/fchem.2021.766107https://doaj.org/article/5446e2a977fb434dabf63311a85d4f082021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fchem.2021.766107/fullhttps://doaj.org/toc/2296-2646Cancer 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.Yoshihide SuzukiKeisuke IchinoheAkihiro SugawaraShinya KidaShinya MuraseJing ZhangOsamu YamadaToshio HattoriYoshiteru OshimaHaruhisa KikuchiHaruhisa KikuchiFrontiers Media S.A.articleimmune checkpoint inhibitorsnatural productsindolePD-L1CTLA-4diversity-enhanced extractsChemistryQD1-999ENFrontiers in Chemistry, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	immune checkpoint inhibitors natural products indole PD-L1 CTLA-4 diversity-enhanced extracts Chemistry QD1-999
spellingShingle	immune checkpoint inhibitors natural products indole PD-L1 CTLA-4 diversity-enhanced extracts Chemistry QD1-999 Yoshihide Suzuki Keisuke Ichinohe Akihiro Sugawara Shinya Kida Shinya Murase Jing Zhang Osamu Yamada Toshio Hattori Yoshiteru Oshima Haruhisa Kikuchi Haruhisa Kikuchi Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts
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	article
author	Yoshihide Suzuki Keisuke Ichinohe Akihiro Sugawara Shinya Kida Shinya Murase Jing Zhang Osamu Yamada Toshio Hattori Yoshiteru Oshima Haruhisa Kikuchi Haruhisa Kikuchi
author_facet	Yoshihide Suzuki Keisuke Ichinohe Akihiro Sugawara Shinya Kida Shinya Murase Jing Zhang Osamu Yamada Toshio Hattori Yoshiteru Oshima Haruhisa Kikuchi Haruhisa Kikuchi
author_sort	Yoshihide Suzuki
title	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_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_sort	development of indole alkaloid-type dual immune checkpoint inhibitors against ctla-4 and pd-l1 based on diversity-enhanced extracts
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5446e2a977fb434dabf63311a85d4f08
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Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts

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