Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry

The
activity of the secreted phosphodiesterase autotaxin produces
the inflammatory signaling molecule LPA and has been associated with
a number of human diseases including idiopathic pulmonary fibrosis
(IPF). We screened a single DNA-encoded chemical library (DECL) of
225 million compounds and identified a series of potent inhibitors.
Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small
molecule. Cocrystallization of compound 1 with human
autotaxin demonstrated that it has a novel binding mode occupying
both the hydrophobic pocket and a channel near the autotaxin active
site. Compound 1 inhibited the production of LPA in human
and mouse plasma at nanomolar levels and showed efficacy in a mouse
model of human lung fibrosis. After successfully completing IND-enabling
studies, compound 1 was approved by the FDA for a Phase
I clinical trial. These results demonstrate that DECL hits can be
readily optimized into clinical candidates.