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j.bbrc.2023.08.050.pdf | 2.7 MB | Adobe PDF | 見る/開く |
タイトル: | Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells |
著者: | Ikeda, Yoshiki Davis, Mindy I. Sumita, Kazutaka Zheng, Yuxiang Kofuji, Satoshi Sasaki, Mika Hirota, Yoshihisa Pragani, Rajan Shen, Min Boxer, Matthew B. Takeuchi, Koh Senda, Toshiya Simeonov, Anton Sasaki, Atsuo T. |
著者名の別形: | 池田, 幸樹 |
キーワード: | KRP203/Mocravimod Drug repurposing Polypharmacology Multitarget drug One drug Multi targets Phosphoinositide metabolism PI3K PI5P4K/Type II PIPK/ phosphatidylinositol 5-phosphate 4-kinase PI3P5K/Type III PIPK/PIKFYVE Drug screening |
発行日: | 30-Oct-2023 |
出版者: | Elsevier BV |
誌名: | Biochemical and Biophysical Research Communications |
巻: | 679 |
開始ページ: | 116 |
終了ページ: | 121 |
抄録: | Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIβ) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kβ, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3, 5)P₂, and PI(3, 4, 5)P₃ levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways. |
著作権等: | © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. |
URI: | http://hdl.handle.net/2433/286791 |
DOI(出版社版): | 10.1016/j.bbrc.2023.08.050 |
PubMed ID: | 37683456 |
出現コレクション: | 学術雑誌掲載論文等 |
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