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

  • J Med Chem. 2019 Oct 24;62(20):9254-9269. doi: 10.1021/acs.jmedchem.9b01213.
Mitsuyasu Kawaguchi  1 ,  Xiang Han  1 ,  Tomoka Hisada  2 ,  Sayaka Nishikawa  2 ,  Kuniyuki Kano  3 ,  Naoya Ieda  1 ,  Junken Aoki  3 ,  Tatsuya Toyama  2 ,  Hidehiko Nakagawa  1
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences , Nagoya City University , 3-1 Tanabe-dori , Mizuho-ku, Nagoya , Aichi 467-8603 , Japan.
  • 2. Graduate School of Medical Sciences, Department of Breast Surgery , Nagoya City University , 1 Kawasumi, Mizuho-cho , Mizuho-ku, Nagoya 467-8601 , Japan.
  • 3. Graduate School of Pharmaceutical Sciences , Tohoku University , 6-3 Aoba, Aramaki , Aoba-ku, Sendai , Miyagi 980-8578 , Japan.
PMID: 31536342 DOI: 10.1021/acs.jmedchem.9b01213
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.

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