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

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.