Discovery and optimization of boronic acid based inhibitors of autotaxin

Harald M H G Albers; Laurens A van Meeteren; David A Egan; Erica W van Tilburg; Wouter H Moolenaar; Huib Ovaa

doi:10.1021/jm1005012

Discovery and optimization of boronic acid based inhibitors of autotaxin

J Med Chem. 2010 Jul 8;53(13):4958-67. doi: 10.1021/jm1005012.

Authors

Harald M H G Albers¹, Laurens A van Meeteren, David A Egan, Erica W van Tilburg, Wouter H Moolenaar, Huib Ovaa

Affiliation

¹ Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

PMID: 20536182
DOI: 10.1021/jm1005012

Abstract

Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in diverse physiological and pathological processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore, targeting ATX with small molecule inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compounds inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC(50) = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Boronic Acids / chemical synthesis*
Boronic Acids / chemistry
Boronic Acids / metabolism
Boronic Acids / pharmacology*
Cell Line
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Lysophosphatidylcholines / metabolism
Magnetic Resonance Spectroscopy
Mass Spectrometry
Multienzyme Complexes / antagonists & inhibitors*
Multienzyme Complexes / metabolism
Phosphodiesterase I / antagonists & inhibitors*
Phosphodiesterase I / metabolism
Phosphoric Diester Hydrolases
Pyrophosphatases / antagonists & inhibitors*
Pyrophosphatases / metabolism
Signal Transduction
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis
Thiazolidinediones / chemistry
Thiazolidinediones / metabolism
Thiazolidinediones / pharmacology

Substances

Boronic Acids
Enzyme Inhibitors
Lysophosphatidylcholines
Multienzyme Complexes
Thiazolidinediones
Phosphoric Diester Hydrolases
Phosphodiesterase I
alkylglycerophosphoethanolamine phosphodiesterase
Pyrophosphatases