5KXA

Selective Inhibition of Autotaxin is Effective in Mouse Models of Liver Fibrosis

Summary for 5KXA

• Entry DOI: 10.2210/pdb5kxa/pdb
• Related: 4ZG6 4ZG7 4ZG9 4ZGA
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (7 entities in total)
• Functional Keywords: enpp2, autotaxin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted : Q13822
• Total number of polymer chains: 1
• Total formula weight: 100003.58

Authors

Stein, A.J.,Bain, G.,Hutchinson, J.H.,Evans, J.F. (deposition date: 2016-07-20, release date: 2016-11-09, Last modification date: 2024-10-23)

Primary citation

Bain, G.,Shannon, K.E.,Huang, F.,Darlington, J.,Goulet, L.,Prodanovich, P.,Ma, G.L.,Santini, A.M.,Stein, A.J.,Lonergan, D.,King, C.D.,Calderon, I.,Lai, A.,Hutchinson, J.H.,Evans, J.F.
Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
J. Pharmacol. Exp. Ther., 360:1-13, 2017

PubMed Abstract: Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.

PubMed: 27754931
DOI: 10.1124/jpet.116.237156

Experimental method

X-RAY DIFFRACTION (2.59 Å)