DataSheet1_Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts.PDF

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.

癌症免疫疗法是借助机体免疫系统开展癌症治疗的手段。近年来，免疫检查点阻断抗体（immune checkpoint-blocking antibodies）已成为部分癌症治疗的核心手段。然而，小分子药物相较于单克隆抗体药物（monoclonal antibody drugs）具备诸多优势，包括细胞穿透性强、半衰期更长、制造成本更低，且可实现口服给药。因此，开发小分子免疫检查点抑制剂（small-molecule immune checkpoint inhibitors）已成为当务之急。此前，我们针对由日本山茱萸（Japanese cornelian cherry）多样性增强提取物制备的合成吲哚生物碱类化合物（indole-alkaloid-type compounds）库进行了筛选，并曾报道一种非天然五环类化合物可抑制细胞毒性T淋巴细胞相关抗原4（CTLA-4）的基因表达。本研究中，我们以该非天然五环类化合物为骨架，通过引入取代基与官能团转化，开发出了效力提升的免疫检查点抑制剂。所开发的化合物不仅可抑制CTLA-4与程序性死亡受体配体1（PD-L1）的基因表达，还能下调细胞表面的蛋白表达水平。尽管其疗效暂未达到现有小分子免疫检查点抑制剂的水平，但据我们所知，本研究开发的化合物是首例被报道的CTLA-4与PD-L1双靶点小分子免疫检查点抑制剂。