Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode

  • J Med Chem. 2017 Jan 26;60(2):722-748. doi: 10.1021/acs.jmedchem.6b01597.
Lisa M Miller  1 ,  Willem-Jan Keune  2 ,  Diana Castagna  1 ,  Louise C Young  3 ,  Emma L Duffy  1 ,  Frances Potjewyd  1 ,  Fernando Salgado-Polo  2 ,  Paloma Engel García  1 ,  Dima Semaan  2 ,  John M Pritchard  4 ,  Anastassis Perrakis  2 ,  Simon J F Macdonald  4 ,  Craig Jamieson  1 ,  Allan J B Watson  1
Affiliations
  • 1. WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • 2. Division of Biochemistry, Netherlands Cancer Institute/Antoni van Leeuwenhoek , Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
  • 3. Strathclyde Institute of Pharmacy and Biomolecular Science, University of Strathclyde , John Arbuthnott Building (Hamnet Wing), 161 Cathedral Street, Glasgow G1 1XL, U.K.
  • 4. Fibrosis Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road, Stevenage SG1 2NY, U.K.
PMID: 27982588 DOI: 10.1021/acs.jmedchem.6b01597
Abstract

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, Cancer, and inflammation, among Others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.