| Literature DB >> 27780639 |
Pritom Shah1, Anne Cheasty1, Caroline Foxton1, Tony Raynham1, Muddasar Farooq1, Irene Farre Gutierrez1, Aurore Lejeune1, Michelle Pritchard1, Andrew Turnbull1, Leon Pang1, Paul Owen1, Susan Boyd1, Alexandra Stowell2, Allan Jordan2, Niall M Hamilton2, James R Hitchin2, Martin Stockley1, Ellen MacDonald1, Mar Jimenez Quesada1, Elisabeth Trivier1, Jana Skeete1, Huib Ovaa3, Wouter H Moolenaar3, Hamish Ryder1.
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.Entities:
Keywords: Autotaxin (ATX); Cancer; Lysophosphatidic acid (LPA); Lysophosphatidylcholine (LPC)
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Year: 2016 PMID： 27780639 DOI： 10.1016/j.bmcl.2016.10.036
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823