Details

Autor(en) / Beteiligte

• Miller, Lisa M
• Keune, Willem-Jan
• Castagna, Diana
• Young, Louise C
• Duffy, Emma L
• Potjewyd, Frances
• Salgado-Polo, Fernando
• Engel García, Paloma
• Semaan, Dima
• Pritchard, John M
• Perrakis, Anastassis
• Macdonald, Simon J. F
• Jamieson, Craig
• Watson, Allan J. B

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2017-01, Vol.60 (2), p.722-748

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.