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

J Med Chem. 2017 Jan 26;60(2):722-748. doi: 10.1021/acs.jmedchem.6b01597. Epub 2017 Jan 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Kinetics
  • Models, Chemical
  • Molecular Docking Simulation
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphoric Diester Hydrolases / chemistry*
  • Picolinic Acids / chemical synthesis
  • Picolinic Acids / chemistry*
  • Structure-Activity Relationship


  • 6-((6-chloro-2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic acid
  • Indoles
  • Phosphodiesterase Inhibitors
  • Picolinic Acids
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase