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

[img]
Preview
 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. ORCID logoORCID: https://orcid.org/0000-0002-0378-1071, Keune, Willem-Jan, Castagna, Diana ORCID logoORCID: https://orcid.org/0000-0003-2315-8073, Young, Louise C., Duffy, Emma L. ORCID logoORCID: https://orcid.org/0000-0002-0502-7216, Potjewyd, Frances ORCID logoORCID: https://orcid.org/0000-0003-4241-9873, Salgado-Polo, Fernando, Garcia, Paloma Engel, Semaan, Dima, Pritchard, John M., Perrakis, Anastassis, Macdonald, Simon J. F., Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272 and Watson, Allan J. B.;
    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:
    CORE (COnnecting REpositories)