jm0c00688_si_001.pdf (857.23 kB)
Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
journal contribution
posted on 2020-07-09, 19:36 authored by John W. Cuozzo, Matthew A. Clark, Anthony D. Keefe, Anna Kohlmann, Mark Mulvihill, Haihong Ni, Louis M. Renzetti, Daniel I. Resnicow, Frank Ruebsam, Eric A. Sigel, Heather A. Thomson, Ce Wang, Zhifeng Xie, Ying ZhangThe
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.