Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode
Miller, Lisa M. and Keune, Willem-Jan and Castagna, Diana and Young, Louise C. and Duffy, Emma L. and Potjewyd, Frances and Salgado-Polo, Fernando and Garcia, Paloma Engel and Semaan, Dima and Pritchard, John M. and Perrakis, Anastassis and Macdonald, Simon J. F. and Jamieson, Craig and Watson, Allan J. B. (2017) Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode. Journal of Medicinal Chemistry, 60 (2). pp. 722-748. ISSN 0022-2623
|
Text (Miller-etal-JMC-2016-Structure-activity-relationships-of-small-molecule-autotaxin-inhibitors)
Miller_etal_JMC_2016_Structure_activity_relationships_of_small_molecule_autotaxin_inhibitors.pdf Accepted Author Manuscript Download (3MB)| Preview |
Abstract
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX we confirm the discrete binding mode.
Creators(s): |
Miller, Lisa M. ![]() ![]() ![]() ![]() ![]() | Item type: | Article |
---|---|
ID code: | 59242 |
Keywords: | autotaxin, cell migration, lysophosphatidic acid, lysophosphatidylcholine, structure-activity relationships, Chemistry, Pharmacy and materia medica, Drug Discovery, Molecular Medicine |
Subjects: | Science > Chemistry Medicine > Pharmacy and materia medica |
Department: | Faculty of Science > Pure and Applied Chemistry Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Strategic Research Themes > Health and Wellbeing |
Depositing user: | Pure Administrator |
Date deposited: | 22 Dec 2016 14:06 |
Last modified: | 01 Jan 2021 12:01 |
Related URLs: | |
URI: | https://strathprints.strath.ac.uk/id/eprint/59242 |
Export data: |