Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Autotaxin produces
the bioactive lipid lysophosphatidic acid (LPA)
and is a drug target of considerable interest for numerous pathologies.
We report the expedient, structure-guided evolution of weak physiological
allosteric inhibitors (bile salts) into potent competitive Autotaxin
inhibitors that do not interact with the catalytic site. Functional
data confirms that our lead compound attenuates LPA mediated signaling
in cells and reduces LPA synthesis in vivo, providing a promising
natural product derived scaffold for drug discovery.