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

Mitsuyasu Kawaguchi, Xiang Han, Tomoka Hisada, Sayaka Nishikawa, Kuniyuki Kano, Naoya Ieda, Junken Aoki, Tatsuya Toyama, Hidehiko Nakagawa

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9254-9269
Number of pages16
JournalJournal of Medicinal Chemistry
Volume62
Issue number20
DOIs
Publication statusPublished - 2019 Oct 24

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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