Structure–Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode

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• 作者：Lisa M. Miller ; Willem-Jan Keune ; Diana Castagna ; Louise C. Young ; Emma L. Duffy ; Frances Potjewyd ; Fernando Salgado-Polo ; Paloma Engel García ; Dima Semaan ; John M. Pritchard ; Anastassis Perrakis ; Simon J. F. Macdonald ; Craig JamiesonAllan J. B. Watson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：722-748
• 全文大小：1103K
• ISSN：1520-4804

文摘

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.