Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells

Yoshiki Ikeda; Mindy I Davis; Kazutaka Sumita; Yuxiang Zheng; Satoshi Kofuji; Mika Sasaki; Yoshihisa Hirota; Rajan Pragani; Min Shen; Matthew B Boxer; Koh Takeuchi; Toshiya Senda; Anton Simeonov; Atsuo T Sasaki

doi:10.1016/j.bbrc.2023.08.050

Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells

Biochem Biophys Res Commun. 2023 Oct 30:679:116-121. doi: 10.1016/j.bbrc.2023.08.050. Epub 2023 Aug 26.

Authors

Affiliations

¹ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
² National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.
³ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Endovascular Surgery, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
⁴ Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10007, USA.
⁵ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
⁶ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
⁷ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Minuma-ku, Saitama, 337-8570, Japan.
⁸ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
⁹ Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, 305-0801, Japan; Department of Accelerator Science, School of High Energy Accelerator Science, The Graduate University for Advanced Studies), Tsukuba, Ibaraki, 305-0801, Japan; Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
¹⁰ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0052, Japan; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH, 45267, USA; Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. Electronic address: sasakiao@ucmail.uc.edu.

PMID: 37683456
PMCID: PMC10559341 (available on 2024-10-30)
DOI: 10.1016/j.bbrc.2023.08.050

Abstract

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)P_2, 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.

Keywords: Drug repurposing; Drug screening; KRP203/Mocravimod; Multi targets; Multitarget drug; One drug; PI3K; PI3P5K/Type III PIPK/PIKFYVE; PI5P4K/Type II PIPK/ phosphatidylinositol 5-phosphate 4-kinase; Phosphoinositide metabolism; Polypharmacology.

Abstract

Grants and funding