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Start Over Author "N. Ieda" Journal journal of medicinal chemistry
3 results on '"N. Ieda"'

1. Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors.

Author

Kawaguchi M, Sekimoto E, Ohta Y, Ieda N, Murakami T, and Nakagawa H

Subjects
Acid Anhydride Hydrolases genetics, Acid Anhydride Hydrolases metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Fluorescent Dyes chemical synthesis, Fluorescent Dyes chemistry, Humans, Molecular Structure, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Structure-Activity Relationship, Acid Anhydride Hydrolases antagonists & inhibitors, Antineoplastic Agents pharmacology, Apoptosis drug effects, Drug Design, Enzyme Inhibitors pharmacology, Fluorescent Dyes pharmacology, Neoplasm Proteins antagonists & inhibitors
Abstract

For the early diagnosis of cancer, leading to a better chance of full recovery, marker genes whose expression is already altered in precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has a unique dinucleoside triphosphate hydrolase (AP 3 Aase) activity, and in this study, we designed and synthesized a series of FHIT fluorescent probes utilizing this activity. We optimized the probe structure for high and specific reactivity with FHIT and applied the optimized probe in a screening assay for FHIT inhibitors. Screening of a compound library with this assay identified several hits. Structural development of a hit compound afforded potent FHIT inhibitors. These inhibitors induce apoptosis in FHIT-expressing cancers via caspase activation. Our results support the idea that FHIT binders, no matter whether inhibitors or agonists of AP 3 Aase activity, might be promising anticancer agents.

Published
2021
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2. Development of an ENPP1 Fluorescence Probe for Inhibitor Screening, Cellular Imaging, and Prognostic Assessment of Malignant Breast Cancer.

Author

Kawaguchi M, Han X, Hisada T, Nishikawa S, Kano K, Ieda N, Aoki J, Toyama T, and Nakagawa H

Subjects
Animals, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Female, Fluorescent Dyes metabolism, Fluorescent Dyes pharmacology, Gene Expression drug effects, Humans, Microscopy, Fluorescence, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Prognosis, Protein Binding, Pyrophosphatases genetics, Pyrophosphatases metabolism, Rats, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Breast Neoplasms diagnosis, Enzyme Inhibitors chemistry, Fluorescent Dyes chemistry, Pyrophosphatases antagonists & inhibitors
Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein that is involved in bone metabolism and insulin resistance, hydrolyzes 2',3'-cGAMP (a STING ligand that promotes innate immunity), and is associated with cancer stemness in breast cancers and glioblastoma. Therefore, ENPP1 is considered a candidate therapeutic target and/or biomarker for early diagnosis of malignant tumors. In this study, we designed and synthesized a sensitive ENPP1 fluorescence probe, Tokyo Green (TG) mAMP. We used it to screen a chemical library for non-phosphate ENPP1 inhibitors. Structural optimization of a selected hit afforded a potent and specific ENPP1 inhibitor. We further found that ENPP1 mRNA expression in tissue samples from patients with triple-negative breast cancer was significantly inversely related to recurrence-free survival (RFS) and overall survival (OS), and TG-mAMP assay revealed a significant difference in ENPP1 activity between ENPP1 high-expressing and ENPP1 low-expressing samples. Our results suggest that TG-mAMP assay might be a rapid and inexpensive tool for predicting the prognosis of patients with malignant breast cancers.

Published
2019
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3. Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin.

Author

Kawaguchi M, Ieda N, and Nakagawa H

Subjects
Amino Acid Sequence, Enzyme Assays, HeLa Cells, Humans, Models, Molecular, Protein Conformation, Amidohydrolases antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemistry, Fluorescent Dyes chemistry, Peptides chemistry, Peptides metabolism, Sirtuins metabolism
Abstract

Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that serve as epigenetic regulators of many physiological processes. Recent studies have shown that in addition to their well-known deacetylase activity, sirtuins also exhibit deacylase activity, such as demyristoylase activity. Here, we show that our previously reported sirtuin fluorescence probe, SFP3, can measure the defatty-acylase activity of SIRT1-3, enabling selective assay of the deacylase activity. We further utilized this finding to develop the first inhibitors of SIRT2 defatty-acylase activity. Notably, most previously reported sirtuin inhibitors, including compound TM, AGK2, and SirReal2, showed almost no SIRT2 defatty-acylase-inhibitory activity, but are essentially specific deacetylase inhibitors. These results suggest that the active sites catalyzing the deacetylase and defatty-acylase activities of sirtuins may be independent.

Published
2019
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