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Discovery of potent inhibitors of the lysophospholipase autotaxin.

Abstract
The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.
AuthorsPritom Shah, Anne Cheasty, Caroline Foxton, Tony Raynham, Muddasar Farooq, Irene Farre Gutierrez, Aurore Lejeune, Michelle Pritchard, Andrew Turnbull, Leon Pang, Paul Owen, Susan Boyd, Alexandra Stowell, Allan Jordan, Niall M Hamilton, James R Hitchin, Martin Stockley, Ellen MacDonald, Mar Jimenez Quesada, Elisabeth Trivier, Jana Skeete, Huib Ovaa, Wouter H Moolenaar, Hamish Ryder
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 22 Pg. 5403-5410 (11 15 2016) ISSN: 1464-3405 [Electronic] England
PMID27780639 (Publication Type: Journal Article)
CopyrightCopyright © 2016 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Lysophospholipids
  • Pyridines
  • Lysophospholipase
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • lysophosphatidic acid
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
  • Crystallography, X-Ray
  • Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology)
  • Humans
  • Lysophospholipase (antagonists & inhibitors, metabolism)
  • Lysophospholipids (metabolism)
  • Mice
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Neoplasms (drug therapy, enzymology)
  • Phosphoric Diester Hydrolases (metabolism)
  • Pyridines (chemistry, pharmacokinetics, pharmacology)

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