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.