Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode

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

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
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Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling 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, amongst 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 using a crystal structure with ATX we confirm the discrete binding mode.
Original languageEnglish
Pages (from-to)722-748
Number of pages27
JournalJournal of Medicinal Chemistry
Issue number2
Early online date16 Dec 2016
Publication statusPublished - 26 Jan 2017


  • autotaxin
  • cell migration
  • lysophosphatidic acid
  • lysophosphatidylcholine
  • structure-activity relationships


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