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Benzoxaboroles-Novel Autotaxin Inhibitors
Kristina Kraljić1, Dubravko Jelić2, Dinko Žiher3
1Fidelta Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia. kristina.kraljic@glpg.com.
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).
Insights
Researchers developed novel benzoxaborole compounds as improved autotaxin (ATX) inhibitors. These compounds show similar potency to existing inhibitors but offer enhanced plasma stability and ADME properties for potential therapeutic applications.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Autotaxin (ATX) is a key enzyme in lysophosphatidylcholine (LPC) hydrolysis to lysophosphatidic acid (LPA).
- LPA signaling pathways are implicated in inflammation, fibrosis, and cancer, making ATX a significant drug target.
- Current ATX inhibitors include Ziritaxestat in clinical trials and boronic acid compounds like HA155 investigated for cancer therapy.
Purpose of the Study:
- To design and synthesize novel ATX inhibitors with improved properties.
- To mimic critical interactions of boronic acid inhibitors using a benzoxaborole warhead.
- To enhance plasma stability by modifying the core spacer structure.
Main Methods:
- Synthesis of benzoxaborole-based compounds designed to inhibit ATX.
- In vitro evaluation of synthesized compounds for ATX inhibitory activity.
- Assessment of ADME (Absorption, Distribution, Metabolism, Excretion) properties, including plasma protein binding, kinetic solubility, and plasma stability.
Main Results:
- Successful synthesis of new benzoxaborole compounds targeting ATX.
- Identification of compound 37, demonstrating comparable ATX inhibition to HA155.
- Compound 37 exhibited improved ADME properties, including better plasma stability and kinetic solubility.
Conclusions:
- Benzoxaborole motif serves as an effective acidic warhead for ATX inhibition.
- The developed benzoxaborole compound 37 offers a promising profile with enhanced stability and ADME characteristics.
- These findings support the potential of compound 37 as a therapeutic agent targeting ATX-related diseases.
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