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

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14 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)2006-2017
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number5
Early online date6 Feb 2017
Publication statusPublished - 9 Mar 2017


  • lipid lysophosphatidic acid
  • autotaxin
  • allosteric inhibitors
  • scaffolds
  • drug discovery
  • catalytic site
  • cell signalling

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