RRC ID 66018
Author Kawaguchi M, Okabe T, Okudaira S, Hama K, Kano K, Nishimasu H, Nakagawa H, Ishitani R, Kojima H, Nureki O, Aoki J, Nagano T.
Title Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain.
Journal J Med Chem
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.
Volume 63(6)
Pages 3188-3204
Published 2020-3-26
DOI 10.1021/acs.jmedchem.9b01967
PMID 32134652
MeSH Animals Catalytic Domain Cell Line, Tumor Cell Movement / drug effects Crystallography, X-Ray Heart Diseases / prevention & control Humans Hydrophobic and Hydrophilic Interactions Imidazoles / chemical synthesis Imidazoles / metabolism Imidazoles / therapeutic use* Male Mice, Inbred C57BL Molecular Structure Phosphodiesterase Inhibitors / chemical synthesis Phosphodiesterase Inhibitors / metabolism Phosphodiesterase Inhibitors / therapeutic use* Phosphoric Diester Hydrolases / metabolism* Protein Binding Pyrimidines / chemical synthesis Pyrimidines / metabolism Pyrimidines / therapeutic use* Structure-Activity Relationship Zebrafish
IF 6.205
Zebrafish Tg(cmlc2:mRFP)ko07