Discovery of potent inhibitors of the lysophospholipase autotaxin

  • Bioorg Med Chem Lett. 2016 Nov 15;26(22):5403-5410. doi: 10.1016/j.bmcl.2016.10.036.
Pritom Shah  1 ,  Anne Cheasty  1 ,  Caroline Foxton  1 ,  Tony Raynham  1 ,  Muddasar Farooq  1 ,  Irene Farre Gutierrez  1 ,  Aurore Lejeune  1 ,  Michelle Pritchard  1 ,  Andrew Turnbull  1 ,  Leon Pang  1 ,  Paul Owen  1 ,  Susan Boyd  1 ,  Alexandra Stowell  2 ,  Allan Jordan  2 ,  Niall M Hamilton  2 ,  James R Hitchin  2 ,  Martin Stockley  1 ,  Ellen MacDonald  1 ,  Mar Jimenez Quesada  1 ,  Elisabeth Trivier  1 ,  Jana Skeete  1 ,  Huib Ovaa  3 ,  Wouter H Moolenaar  3 ,  Hamish Ryder  1
Affiliations
  • 1. Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
  • 2. Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
  • 3. Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
PMID: 27780639 DOI: 10.1016/j.bmcl.2016.10.036
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.

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