John W. Cuozzo; Matthew A. Clark; Anthony D. Keefe; Anna Kohlmann; Mark J Mulvihill; Haihong Ni; Louis Renzetti; Daniel I. Resnicow; Frank Ruebsam; Eric A. Sigel; Heather A. Thomson; Ce Wang; Zhifeng Xie; Ying Zhang
J. Med. Chem., 2020, 63, 14, 7840-7856
https://doi.org/10.1021/acs.jmedchem.0c00688

Abstract

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 and selective inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective and bioavailable small molecule. Co-crystallization 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.