TY - JOUR
T1 - Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode
AU - Miller, Lisa M.
AU - Keune, Willem-Jan
AU - Castagna, Diana
AU - Young, Louise C.
AU - Duffy, Emma L.
AU - Potjewyd, Frances
AU - Salgado-Polo, Fernando
AU - Garcia, Paloma Engel
AU - Semaan, Dima
AU - Pritchard, John M.
AU - Perrakis, Anastassis
AU - Macdonald, Simon J. F.
AU - Jamieson, Craig
AU - Watson, Allan J. B.
N1 - We thank GlaxoSmithKline for the Ph.D. studentships (L.M.M., D.C., E.L.D., and F.P.), as well as chemical and analytical resources. L.M.M. thanks BMCS-RSC (travel grant 2016) and SAGES (PEER grant 2016) for funding.
PY - 2017/1/26
Y1 - 2017/1/26
N2 - 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.
AB - 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.
KW - Autotaxin
KW - Cell migration
KW - Lysophosphatidic acid
KW - Lysophosphatidylcholine
KW - Structure-activity relationships
U2 - 10.1021/acs.jmedchem.6b01597
DO - 10.1021/acs.jmedchem.6b01597
M3 - Article
SN - 0022-2623
VL - 60
SP - 722
EP - 748
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -
