Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode

Miller, Lisa M. and Keune, Willem-Jan and Castagna, Diana and Young, Louise C. and Duffy, Emma L. and Potjewyd, Frances and Salgado-Polo, Fernando and Garcia, Paloma Engel and Semaan, Dima and Pritchard, John M. and Perrakis, Anastassis and Macdonald, Simon J. F. and Jamieson, Craig and Watson, Allan J. B. (2017) Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode. Journal of Medicinal Chemistry, 60 (2). pp. 722-748. ISSN 0022-2623 (

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Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling 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, amongst 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 using a crystal structure with ATX we confirm the discrete binding mode.


Miller, Lisa M. ORCID logoORCID:, Keune, Willem-Jan, Castagna, Diana ORCID logoORCID:, Young, Louise C., Duffy, Emma L. ORCID logoORCID:, Potjewyd, Frances ORCID logoORCID:, Salgado-Polo, Fernando, Garcia, Paloma Engel, Semaan, Dima, Pritchard, John M., Perrakis, Anastassis, Macdonald, Simon J. F., Jamieson, Craig ORCID logoORCID: and Watson, Allan J. B.;