title: A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinases.
abstract: Pantothenate kinase (PanK) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. The association of PanK with neurodegeneration and diabetes suggests that chemical modifiers of PanK activity may be useful therapeutics. We performed a high throughput screen of >520000 compounds from the St. Jude compound library and identified new potent PanK inhibitors and activators with chemically tractable scaffolds. The HTS identified PanK inhibitors exemplified by the detailed characterization of a tricyclic compound (7) and a preliminary SAR. Biophysical studies reveal that the PanK inhibitor acts by binding to the ATP-enzyme complex.
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Infectious Diseases, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.
authors.forename: Lalit Kumar
authors.initials: LK
authors.lastname: Sharma
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Boyd
authors.forename: Asli
authors.initials: A
authors.lastname: Goktug
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
mesh_terms: D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase