title: Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode.
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.
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Miller
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute/Antoni van Leeuwenhoek , Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Diana
authors.initials: D
authors.lastname: Castagna
authors.affiliation: Strathclyde Institute of Pharmacy and Biomolecular Science, University of Strathclyde , John Arbuthnott Building (Hamnet Wing), 161 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Young
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duffy
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Frances
authors.initials: F
authors.lastname: Potjewyd
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute/Antoni van Leeuwenhoek , Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Salgado-Polo
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Paloma
authors.initials: P
authors.lastname: Engel García
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute/Antoni van Leeuwenhoek , Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Dima
authors.initials: D
authors.lastname: Semaan
authors.affiliation: Fibrosis Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: John M
authors.initials: JM
authors.lastname: Pritchard
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute/Antoni van Leeuwenhoek , Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.affiliation: Fibrosis Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road, Stevenage SG1 2NY, U.K.
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Craig
authors.identifier: 0000-0002-6567-8272
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
authors.forename: Allan J B
authors.identifier: 0000-0002-1582-4286
authors.initials: AJ
authors.lastname: Watson
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
chemical_list: D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D010848:Picolinic Acids; D000099189:Lysophospholipase D; C000620975:6-((6-chloro-2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)picolinic acid