Identification of Potent in Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain

Mitsuyasu Kawaguchi, Takayoshi Okabe, Shinichi Okudaira, Kotaro Hama, Kuniyuki Kano, Hiroshi Nishimasu, Hidehiko Nakagawa, Ryuichiro Ishitani, Hirotatsu Kojima, Osamu Nureki, Junken Aoki, Tetsuo Nagano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.

Original languageEnglish
Pages (from-to)3188-3204
Number of pages17
JournalJournal of Medicinal Chemistry
Volume63
Issue number6
DOIs
Publication statusPublished - 2020 Mar 26

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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