Discovery of potent inhibitors of the lysophospholipase autotaxin

Article

Shah, Pritom, Cheasty, Anne, Foxton, Caroline, Raynham, T., Farooq, Muddasar, Gutierrez, Irene Farre, Lejeune, Aurore, Pritchard, Michelle, Turnbull, Andrew, Pang, Leon, Owen, Paul, Boyd, Susan, Stowell, Alexandra, Jordan, Allan, Hamilton, Niall M., Hitchin, James R., Stockley, Martin, MacDonald, Ellen, Quesada, Mar Jimenez, Trivier, Elisabeth, Skeete, Jana, Ovaa, Huib, Moolenaar, Wouter H. and Ryder, Hamish 2016. Discovery of potent inhibitors of the lysophospholipase autotaxin. Bioorganic & Medicinal Chemistry Letters. 26 (22), pp. 5403-5410. https://doi.org/10.1016/j.bmcl.2016.10.036
AuthorsShah, Pritom, Cheasty, Anne, Foxton, Caroline, Raynham, T., Farooq, Muddasar, Gutierrez, Irene Farre, Lejeune, Aurore, Pritchard, Michelle, Turnbull, Andrew, Pang, Leon, Owen, Paul, Boyd, Susan, Stowell, Alexandra, Jordan, Allan, Hamilton, Niall M., Hitchin, James R., Stockley, Martin, MacDonald, Ellen, Quesada, Mar Jimenez, Trivier, Elisabeth, Skeete, Jana, Ovaa, Huib, Moolenaar, Wouter H. and Ryder, Hamish
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.

KeywordsAutotaxin (ATX); Lysophosphatidic acid (LPA); Lysophosphatidylcholine (LPC); Cancer
JournalBioorganic & Medicinal Chemistry Letters
Journal citation26 (22), pp. 5403-5410
ISSN0960-894X
Year2016
PublisherElsevier
Digital Object Identifier (DOI)https://doi.org/10.1016/j.bmcl.2016.10.036
Web address (URL)https://doi.org/10.1016/j.bmcl.2016.10.036
Publication dates
Print14 Oct 2016
Publication process dates
Deposited09 Aug 2017
Accepted12 Oct 2016
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