期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 2, 页码 722-748出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01597
关键词
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资金
- BMCS-RSC
- SAGES (PEER grant)
- Engineering and Physical Sciences Research Council [1521810] Funding Source: researchfish
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.
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