Abstract
Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability).
Highlights
Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyses the bioactive lipid molecule lysophosphatidylcholine (LPC) to form lysophosphatidic acid (LPA) and choline (Figure 1) [1]
Inhibition suggested for SAR transfer between series of active compounds, targeting this hydrogen bond can be useful in the modification of this class of benzoxaboroles [22]
The group occupying the hydrophobic lipid-binding pocket was optimally that of the Pfizer molecule PF-8380
Summary
Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyses the bioactive lipid molecule lysophosphatidylcholine (LPC) to form lysophosphatidic acid (LPA) and choline (Figure 1) [1]. LPA modulates six different G protein-coupled receptors (GPCRs) in the cell membrane. It has been reported that LPA has pro-tumorigenic effects on ovarian, breast and prostate cancer cells [4]. High levels of LPA have been found in the peritoneal liquids (ascites) of women suffering from ovarian cancer [5]. High levels of LPA (up to 10 times higher than normal) have generally been observed in cancer patients compared to healthy subjects [6]. Nagano reported that a 4 mg/kg i.v. injection of an ATX inhibitor (such as 3BoA) significantly decreases LPA plasma levels (almost to zero), indicating that ATX is the major enzyme responsible for LPA production [7]
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