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PDBsum entry 3wav
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Hydrolase/hydrolase inhibitor
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PDB id
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3wav
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References listed in PDB file
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Key reference
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Title
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Screening and X-Ray crystal structure-Based optimization of autotaxin (enpp2) inhibitors, Using a newly developed fluorescence probe.
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Authors
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M.Kawaguchi,
T.Okabe,
S.Okudaira,
H.Nishimasu,
R.Ishitani,
H.Kojima,
O.Nureki,
J.Aoki,
T.Nagano.
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Ref.
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Acs Chem Biol, 2013,
8,
1713-1721.
[DOI no: ]
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PubMed id
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Abstract
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Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase
2 (ENPP2), was originally identified as a tumor cell autocrine motility factor
and was found to be identical to plasma lysophospholipase D, which is the
predominant contributor to lysophosphatidic acid (LPA) production from
lysophospholipids. ATX is therefore considered to regulate the physiological and
pathological roles of LPA, including angiogenesis, lymphocyte trafficking,
tissue fibrosis, and cancer cell invasion and metastasis. Thus, it is a
potential therapeutic target. Here, we first developed a sensitive and specific
ATX fluorescence probe, TG-mTMP, and used it to screen ATX inhibitors in a large
chemical library. This probe, which is superior to previously available probes
FS-3 and CPF4 in terms of sensitivity or specificity, enabled us to identify
several novel ATX inhibitor scaffolds. We solved the crystal structures of ATX
complexes with the hit compounds at high resolution (1.75-1.95 Å) and used this
information to guide optimization of the structure of a selected inhibitor. The
optimized compounds, 3BoA and its derivatives, exhibited potent ATX-inhibitory
activity both in vitro and in vivo. These inhibitors are expected to be useful
tools to understand the roles of ATX in vitro and in vivo and may also be
candidate anti-ATX therapeutic agents.
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