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Updated: Mar 10, 2026

Mapping the Binding Site of an Aptamer on ATP Using MicroScale Thermophoresis
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Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode

Lisa M Miller1, Willem-Jan Keune2, Diana Castagna1

  • 1WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.

Journal of Medicinal Chemistry
|December 17, 2016
PubMed

Insights

Autotaxin (ATX) inhibitors targeting the ATX-LPA pathway offer therapeutic potential. This study reveals novel noncompetitive ATX inhibitors with a unique binding mode, distinct from typical lipid-like compounds.

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Autotaxin (ATX) is a key enzyme in lysophosphatidylcholine (LPC) hydrolysis to lysophosphatidic acid (LPA).
  • The ATX-LPA signaling pathway is crucial for cell survival, migration, and proliferation.
  • ATX inhibition is a therapeutic strategy for fibrotic diseases, cancer, and inflammation.

Purpose of the Study:

  • To investigate the structure-activity relationships (SAR) of a novel class of small molecule ATX inhibitors.
  • To characterize the inhibition mechanism of these ATX analogues.
  • To elucidate the binding mode of these inhibitors to ATX.

Main Methods:

  • Enzyme kinetics studies to determine inhibition type.
  • Crystallography to obtain the ATX-inhibitor complex structure.
  • Synthesis and characterization of ATX inhibitor analogues.

Main Results:

  • Analogues of the reported chemotype act as noncompetitive inhibitors of ATX.
  • Enzyme kinetics confirmed a noncompetitive inhibition mechanism.
  • A crystal structure revealed a discrete binding mode, distinct from the native ligand's scaffold.

Conclusions:

  • The developed small molecules represent a novel class of noncompetitive ATX inhibitors.
  • These findings provide a structural basis for designing new ATX inhibitors with unique binding characteristics.
  • This research expands the chemical space for targeting the ATX-LPA pathway.

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