Download MendeleyNovel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.
Cuozzo, J.W., Clark, M.A., Keefe, A.D., Kohlmann, A., Mulvihill, M., Ni, H., Renzetti, L.M., Resnicow, D.I., Ruebsam, F., Sigel, E.A., Thomson, H.A., Wang, C., Xie, Z., Zhang, Y.(2020) J Med Chem 63: 7840-7856
- PubMed: 32584034
- DOI: https://doi.org/10.1021/acs.jmedchem.0c00688
- Primary Citation of Related Structures:
6W35 - PubMed 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 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.
Organizational Affiliation:
X-Chem, Inc., 100 Beaver Street, Suite 101, Waltham, Massachusetts 02543, United States.
