6w35 | pdb_00006w35

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

spinqualitylabelsall models 6w35, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.98Å Ligands: BMA, CA, CL, IOD, MAN, MG, NAG, SCN, SKV, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. A Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.,Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill MJ, Ni H, Renzetti L, Resnicow DI, Ruebsam F, Sigel EA, Thomson HA, Wang C, Xie Z, Zhang Y J Med Chem. 2020 Jun 25. doi: 10.1021/acs.jmedchem.0c00688. PMID:32584034 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures

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