Title : Screening and X-ray crystal structure-based optimization of
autotaxin (
ENPP2 ) inhibitors, using a newly developed fluorescence probe
Abstract :
- 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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