Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

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...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 60; no. 5; pp. 2006 - 2017
Main Authors:	Keune, Willem-Jan, Potjewyd, Frances, 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, Perrakis, Anastassis
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 09-03-2017
Subjects:	Allosteric Regulation Carbon-13 Magnetic Resonance Spectroscopy Crystallization Mass Spectrometry Molecular Structure Phosphoric Diester Hydrolases - drug effects Proton Magnetic Resonance Spectroscopy
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.6b01743