Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts

Suzuki, Yoshihide and Ichinohe, Keisuke and Sugawara, Akihiro and Kida, Shinya and Murase, Shinya and Zhang, Jing and Yamada, Osamu and Hattori, Toshio and Oshima, Yoshiteru and Kikuchi, Haruhisa (2021) Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts. Frontiers in Chemistry, 9. ISSN 2296-2646

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Abstract

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.

Item Type: Article
Subjects: European Scholar > Chemical Science
Depositing User: Managing Editor
Date Deposited: 29 Nov 2022 05:06
Last Modified: 23 Sep 2024 05:20
URI: http://article.publish4promo.com/id/eprint/454

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