Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.


Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.

More about this publication

Journal of medicinal chemistry
  • Volume 65
  • Issue nr. 8
  • Pages 6338-6351
  • Publication date 28-04-2022

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