Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

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Keune, Willem-Jan and Potjewyd, Frances and Heidebrecht, Tatjana and Salgado-Polo, Fernando and Macdonald, Simon J. F. and Chelvarajan, Lakshman and Abdel Latif, Ahmed and Soman, Sony and Morris, Andrew J. and Watson, Allan J. B. and Jamieson, Craig and Perrakis, Anastassis (2017) Rational design of autotaxin inhibitors by structural evolution of endogenous modulators. Journal of Medicinal Chemistry, 60 (5). pp. 2006-2017. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.6b01743)

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Abstract

Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA), and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signalling in cells, and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

ORCID iDs

Keune, Willem-Jan, Potjewyd, Frances ORCID logoORCID: https://orcid.org/0000-0003-4241-9873, Heidebrecht, Tatjana, Salgado-Polo, Fernando, Macdonald, Simon J. F., Chelvarajan, Lakshman, Abdel Latif, Ahmed, Soman, Sony, Morris, Andrew J., Watson, Allan J. B., Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272 and Perrakis, Anastassis;
  • Item type:Article
    ID code:59722
    Dates:
    Date
    Event
    9 March 2017
    Published
    6 February 2017
    Published Online
    6 February 2017
    Accepted
    Notes:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01743
    Subjects:Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Pure and Applied Chemistry
    Strategic Research Themes > Health and Wellbeing
    Depositing user: Pure Administrator
    Date deposited:07 Feb 2017 10:45
    Last modified:11 Nov 2024 11:37
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/59722
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