title: Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition.
abstract: Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4μM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1-5 GPCR.
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Ragle
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Palanisamy
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Margaux J
authors.initials: MJ
authors.lastname: Joe
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Stein
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center, 894 Union Avenue, Memphis, TN 38163, United States.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center, 894 Union Avenue, Memphis, TN 38163, United States.
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Baker
authors.affiliation: Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN 38152, United States.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D000099189:Lysophospholipase D
chemical_list: D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
keywords: Autotaxin; Pharmacophore; Structure–activity relationship