TY - JOUR
T1 - Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts
AU - Suzuki, Yoshihide
AU - Ichinohe, Keisuke
AU - Sugawara, Akihiro
AU - Kida, Shinya
AU - Murase, Shinya
AU - Zhang, Jing
AU - Yamada, Osamu
AU - Hattori, Toshio
AU - Oshima, Yoshiteru
AU - Kikuchi, Haruhisa
N1 - Funding Information:
This work was supported in part by the Grants-in-Aid for Scientific Research (Nos. 16H03279 and 19H02837) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; the Takeda Science Foundation; Suzuken Memorial Foundation; the Uehara Memorial Foundation; Tokyo Biochemical Research Foundation; and Hokuto Foundation for Bioscience.
Publisher Copyright:
© Copyright © 2021 Suzuki, Ichinohe, Sugawara, Kida, Murase, Zhang, Yamada, Hattori, Oshima and Kikuchi.
PY - 2021/11/8
Y1 - 2021/11/8
N2 - 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.
AB - 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.
KW - CTLA-4
KW - PD-L1
KW - diversity-enhanced extracts
KW - immune checkpoint inhibitors
KW - indole
KW - natural products
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U2 - 10.3389/fchem.2021.766107
DO - 10.3389/fchem.2021.766107
M3 - Article
AN - SCOPUS:85119607805
SN - 2296-2646
VL - 9
JO - Frontiers in Chemistry
JF - Frontiers in Chemistry
M1 - 766107
ER -