title: Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells.
abstract: Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50∼ 32 nM; 3b, IC50∼ 9 nM; and 14, IC50∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC50∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA1G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Sue Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Truc Chi T
authors.initials: TC
authors.lastname: Pham
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Baker
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Gabor J
authors.initials: GJ
authors.lastname: Tigyi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.|Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
authors.forename: Duane D
authors.identifier: 0000-0002-6093-0985
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D000096926:Benzenesulfonamides; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D013449:Sulfonamides; D000096926:Benzenesulfonamides; D000099189:Lysophospholipase D