Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Willem Jan Keune, Frances Potjewyd, Tatjana Heidebrecht, Fernando Salgado-Polo, Simon J.F. Macdonald, Lakshman Chelvarajan, Ahmed Abdel Latif, Sony Soman, Andrew J. Morris, Allan J.B. Watson, Craig Jamieson, Anastassis Perrakis

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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 signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

Original languageEnglish
Pages (from-to)2006-2017
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number5
StatePublished - Mar 9 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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