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

Published on Oct 24, 2019in Journal of Medicinal Chemistry7.446
· DOI :10.1021/ACS.JMEDCHEM.9B01213
Mitsuyasu Kawaguchi13
Estimated H-index: 13
 (Nagoya City University), Xiang Han1
Estimated H-index: 1
 (Nagoya City University)+ 6 AuthorsHidehiko Nakagawa33
Estimated H-index: 33
 (Nagoya City University)
Sources
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-exp...
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References48
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Jan 1, 2019·American Journal of Cancer Research6.17
#1Min Hu (SJTU: Shanghai Jiao Tong University)H-Index: 9
#2Wenzheng Guo (Tongji University)H-Index: 12
Last. Jiong DengH-Index: 23
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Induction of cancer stem cell (CSC) characters and epithelial mesenchymal transition (EMT) features are crucial in tumor initiation, progression and metastasis. However, underlying mechanisms remain incompletely understood. Here, we showed that ENPP1 plays an important role in inducing and maintaining EMT phenotypes and CSC features in lung cancer. ENPP1 is upregulated in lung cancer cells. ENPP1-knockdown in lung cancer HCC827 cells and A549 cells resulted in suppressed colonogenic formation, a...
Dec 1, 2018·EMBO Reports8.81
#1Li Teng Khoo (AS: Academia Sinica)H-Index: 1
#2Liuh‐Yow Chen (AS: Academia Sinica)H-Index: 1
Abstract The cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway mediates anti‐microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self‐DNA from tumors and by‐products of genomic instability also activates the cGAS–STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists...
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Nov 7, 2018·Nature49.96
#1Ramanjulu Joshi M (GSK: GlaxoSmithKline)H-Index: 6
#2George Scott Pesiridis (GSK: GlaxoSmithKline)H-Index: 1
Last. H.C. Eberl (GSK: GlaxoSmithKline)H-Index: 1
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Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have prog...
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Oct 24, 2018·Nature Communications14.92
#7Ryuichiro Ishitani (UTokyo: University of Tokyo)H-Index: 63
ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2′3′-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3′3′-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3′3′-cGAMP and the reacti...
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#1Mohan R KaadigeH-Index: 1
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Apr 22, 2018·Journal of Medicinal Chemistry7.45
#1Vadim Zelikman (BIU: Bar-Ilan University)H-Index: 1
#2Julie Pelletier (Laval University)H-Index: 17
Last. Bilha Fischer (BIU: Bar-Ilan University)H-Index: 29
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Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) hydrolyzes phosphodiester bonds of nucleotides such as ATP, resulting mainly in the formation of AMP and pyrophosphate. NPP1 activity plays a deleterious function in calcified aortic valve disease and calcium pyrophosphate deposition disease. Thus, inhibitors of NPP1 represent a medical need. We developed novel NPP1 inhibitors based on uridine 5′-Pα,α-dithiophosphate analogues, 9–12. All these analogues potently inhibited hNPP1 (80–100% i...
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May 24, 2017·MedChemComm3.60
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Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC 3.1.4.1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, e.g. in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5′-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. The enzyme is involved in various biological processes including bone mineralization,...
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#1Indulekha C. L. PillaiH-Index: 3
#2Shen LiH-Index: 6
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Summary Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcifica...
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#1Kenji Chamoto (Kyoto University)H-Index: 31
#2Muna Al-Habsi (Kyoto University)H-Index: 1
Last. Tasuku Honjo (Kyoto University)H-Index: 155
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Immunity developed to defend our bodies from foreign particles, including bacteria and viruses. Although effector cells responsible for acquired immunity, mainly T cells, and B cells, are able to distinguish self from non-self, they sometimes attack the body’s tissues because of imperfect central tolerance. Several immune check points developed to limit overactivation of these cells. One of the most important immune checkpoints is programmed cell death-1 (PD-1), which is expressed mainly on acti...
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#1André Rolim Belisário (UFMG: Universidade Federal de Minas Gerais)H-Index: 7
#2Rahyssa Rodrigues Sales (UFMG: Universidade Federal de Minas Gerais)H-Index: 4
Last. Marcos Borato Viana (UFMG: Universidade Federal de Minas Gerais)H-Index: 26
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To the editor: Transcranial Doppler (TCD) screening and intensification therapy may reduce the risk of stroke from 11% to 1.9% in children with sickle cell anemia (SCA).[1][1] However, the relatively low specificity of TCD screening in identifying individuals at risk of stroke[2][2] highlights the
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Biosensors have been flourishing in the field of drug discovery with pronounced developments in the past few years. They facilitate the screening and discovery of innovative drugs. However, there is still a lack of critical reviews that compare the merits and shortcomings of these biosensors from a pharmaceutical point of view. This contribution presents a critical and up-to-date overview on the recent progress of tailored biosensors, including surface plasmon resonance, fluorescent, photoelectr...
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Jun 29, 2021·Organic chemistry frontiers5.28
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Jun 23, 2021·Journal of Medicinal Chemistry7.45
#1Mitsuyasu Kawaguchi (Nagoya City University)H-Index: 13
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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 (AP3Aase) 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...
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May 5, 2021·European Journal of Medicinal Chemistry6.51
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#2Mohammed I. El-Gamal (UOS: University of Sharjah)H-Index: 21
Last. Jamshed Iqbal (CUI: COMSATS Institute of Information Technology)H-Index: 25
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Abstract Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthe...
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Immune cells sense bacteria-derived c-di-GMP and c-di-AMP as well as host-derived cGAMP, which is synthesized by cGAS upon binding to the pathogen's DNA, to mount an immunological response (cytokine production) via the STING-TBK1 pathway. Successful pathogens, such as Mycobacterium tuberculosis and group B streptococcus, harbor phosphodiesterases (PDEs) that can cleave bacterial c-di-AMP as well as host-derived cGAMP to blunt the host's response to infection. Selective inhibitors of bacterial cy...
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#1Meera KumarH-Index: 5
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The innate immune response to cancer is initiated by cytosolic DNA, where it binds to cGAS and triggers type I interferon (IFN) expression via the STING receptor, leading to activation of tumor-specific T cells. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as the primary enzyme responsible for degrading cGAMP, and therefore it is under intense investigation as a therapeutic target for cancer immunotherapy. ENPP1 hydrolyzes cGAMP to produce AMP and GMP, and hydro...
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Nov 1, 2020·Bioorganic Chemistry5.28
#1Hanan S. Anbar (Dubai Pharmacy College)H-Index: 8
#2Randa El-GamalH-Index: 3
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Abstract Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzo...
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Mar 21, 2020·Bioorganic Chemistry5.28
#1Saif Ullah (CUI: COMSATS Institute of Information Technology)H-Index: 4
#2Mohammed I. El-Gamal (UOS: University of Sharjah)H-Index: 21
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Abstract A series of six compounds (1a-f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzenesulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and -3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e are the most potent inhibitors of ENPP1 with sub-micromolar IC50 values (0.69, 0.18, and 0.40 µM, respectively. Moreover, compound 1b is the most potent inhibitor of E...
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