Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

  • J Med Chem. 2017 Mar 9;60(5):2006-2017. doi: 10.1021/acs.jmedchem.6b01743.
Willem-Jan Keune  1 ,  Frances Potjewyd  2 ,  Tatjana Heidebrecht  1 ,  Fernando Salgado-Polo  1 ,  Simon J F Macdonald  3 ,  Lakshman Chelvarajan  4 ,  Ahmed Abdel Latif  4 ,  Sony Soman  4 ,  Andrew J Morris  4 ,  Allan J B Watson  2 ,  Craig Jamieson  2 ,  Anastassis Perrakis  1
Affiliations
  • 1. Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
  • 2. Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
  • 3. GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 4. Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington Veterans Affairs Medical Center , Lexington Kentucky 40536, United States.
PMID: 28165241 DOI: 10.1021/acs.jmedchem.6b01743
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 signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.