Autotaxin inhibitors: a patent review (2012-2016)

Abstract

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases. Areas covered: This review article summarizes the autotaxin inhibitors presented in patent literature from October 2012 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo. Expert opinion: During the recent years, there has been an intensive effort on the discovery of potent and selective ATX inhibitors. Although various synthetic inhibitors have been developed, only limited studies for their in vivo activity have been reported so far. A decade after the first claim of synthetic ATX inhibitors in 2006, one inhibitor has been in clinical trials for idiopapthic pulmonary fibrosis. The use of ATX inhibitors seems an attractive strategy to produce novel medicinal agents, for example anticancer agents.

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

“…Activity-based lead discovery campaigns, using artificial substrates as activity reporters, subsequently made important contributions, many of which are reviewed in e.g. [35,36]. The structural characterization of rat and mouse ATX structures in 2011 [24,26], enabled a remarkable potential for selective inhibitor design by focusing on the three dimensional architecture of the ATX active site.…”

The Autotaxin - Lysophosphatidic Acid Axis as a Novel Therapeutic Target for Liver Fibrosis

“…The receptor LPA 5 mediates stress fiber formation, neurite retraction, and receptor internalization through its G-proteins. It is highly expressed in the spleen, and low levels are found in the heart, colon, placenta, and liver [19,49,50]. The most recently discovered LPA receptor is LPA 6 .…”

Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis

“…Recently, lots of patents and literature reported numerous ATX inhibitors with probable application for the treatment of diverse pathologies [10,14,[20][21][22]. For example, Nicolas Desroy identified a first-in-class ATX inhibitor, GLPG1690, which has been undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis [14].…”