6W35

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

6W35 の概要

• エントリーDOI: 10.2210/pdb6w35/pdb
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase 2, IODIDE ION, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: autotaxin, lipid binding protein
• 由来する生物種: Pan troglodytes (Chimpanzee)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 97774.61

構造登録者

Cuozzo, J.W. (登録日: 2020-03-09, 公開日: 2020-07-08, 最終更新日: 2024-10-16)

主引用文献

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.
Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.
J.Med.Chem., 63:7840-7856, 2020

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 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 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 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 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.

PubMed: 32584034
DOI: 10.1021/acs.jmedchem.0c00688

実験手法

X-RAY DIFFRACTION (1.98 Å)