Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Suzuki, Yoshihide, Ichinohe, Keisuke, Sugawara, Akihiro, Kida, Shinya, Murase, Shinya, Zhang, Jing, Yamada, Osamu, Hattori, Toshio, Oshima, Yoshiteru, Kikuchi, Haruhisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
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
_version_ 1784607398753730560
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
work_keys_str_mv AT suzukiyoshihide developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT ichinohekeisuke developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT sugawaraakihiro developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT kidashinya developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT muraseshinya developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT zhangjing developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT yamadaosamu developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT hattoritoshio developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT oshimayoshiteru developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts
AT kikuchiharuhisa developmentofindolealkaloidtypedualimmunecheckpointinhibitorsagainstctla4andpdl1basedondiversityenhancedextracts