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.

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