Discovery of potent inhibitors of the lysophospholipase autotaxin.
Authors
Shah, PCheasty, A
Foxton, C
Raynham, T
Farooq, M
Gutierrez, I
Lejeune, A
Pritchard, M
Turnbull, A
Pang, L
Owen, P
Boyd, S
Stowell, Alexandra I J
Jordan, Allan M
Hamilton, Niall M
Hitchin, James R
Stockley, M
MacDonald, E
Quesada, M
Trivier, E
Skeete, J
Ovaa, H
Moolenaar, W
Ryder, H
Affiliation
Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UKIssue Date
2016-10-14
Metadata
Show full item recordAbstract
The autotoxin-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 of ATX together with the occupying the LPA 'exit' channel.Citation
Discovery of potent inhibitors of the lysophospholipase autotaxin. 2016 Bioorg. Med. Chem. Lett.Journal
Bioorganic & Medicinal Chemistry LettersDOI
10.1016/j.bmcl.2016.10.036PubMed ID
27780639Type
ArticleISSN
1464-3405ae974a485f413a2113503eed53cd6c53
10.1016/j.bmcl.2016.10.036