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Discovery of potent inhibitors of the lysophospholipase autotaxin

DOI: 10.1016/j.bmcl.2016.10.036 DOI Help

Authors: Pritom Shah (Cancer Research Technology) , Anne Cheasty (Cancer Research Technology) , Caroline Foxton (Cancer Research Technology) , Tony Raynham (Cancer Research Technology) , Muddasar Farooq (Cancer Research Technology) , Irene Farre Gutierrez (Cancer Research Technology) , Aurore Lejeune (Cancer Research Technology) , Michelle Pritchard (Cancer Research Technology) , Andrew Turnbull (Cancer Research Technology) , Leon Pang (Cancer Research Technology) , Paul Owen (Cancer Research Technology) , Susan Boyd (Cancer Research Technology) , Alexandra Stowell (Cancer Research UK Manchester Institute, The University of Manchester) , Allan Jordan (Cancer Research UK Manchester Institute, The University of Manchester) , Niall M. Hamilton (Cancer Research UK Manchester Institute, The University of Manchester) , James R. Hitchin (Cancer Research UK Manchester Institute, The University of Manchester) , Martin Stockley (Cancer Research Technology) , Ellen Macdonald (Cancer Research Technology) , Mar Jimenez Quesada (Cancer Research Technology) , Elisabeth Trivier (Cancer Research Technology) , Jana Skeete (Cancer Research Technology) , Huib Ovaa (Netherlands Cancer Institute) , Wouter H. Moolenaar (Netherlands Cancer Institute) , Hamish Ryder (Cancer Research Technology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 26 , PAGES 5403 - 5410

State: Published (Approved)
Published: November 2016

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.

Journal Keywords: Autotaxin (ATX); Lysophosphatidic acid (LPA); Lysophosphatidylcholine (LPC); Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography