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

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    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.

    Author(s):Miller, Lisa M. ORCID: https://orcid.org/0000-0002-0378-1071, Keune, Willem-Jan, Castagna, Diana ORCID: https://orcid.org/0000-0003-2315-8073, Young, Louise C., Duffy, Emma L. ORCID: https://orcid.org/0000-0002-0502-7216, Potjewyd, Frances ORCID: 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: 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:11 Aug 2019 00:37
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/59242
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