title: Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes.
abstract: Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified-one tissue-nonspecific (TNAP) and three tissue-specific-named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Bobkova
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Tina
authors.initials: T
authors.lastname: Kiffer-Moreira
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Brock
authors.initials: B
authors.lastname: Brown
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Santhi
authors.initials: S
authors.lastname: Ganji
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zou
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Ian
authors.initials: I
authors.lastname: Pass
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Flávia Godoy
authors.initials: FG
authors.lastname: Iano
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Craig
authors.initials: C
authors.lastname: Rosenstein
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Anton
authors.initials: A
authors.lastname: Cheltsov
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Justin
authors.initials: J
authors.lastname: Rascon
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Carlton
authors.initials: C
authors.lastname: Gasior
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Anita
authors.initials: A
authors.lastname: Forster
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Shi
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.affiliation: UCLA School of Medicine, Los Angeles, CA 90095.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Thomas D Y
authors.initials: TDY
authors.lastname: Chung
authors.affiliation: UCLA School of Medicine, Los Angeles, CA 90095.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaunitz
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000083:Acetanilides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D051379:Mice; D020033:Protein Isoforms / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; C000592757:N-(2,5-dimethylphenyl)-2-(2-oxo-2,3-dihydrobenzo(d)oxazole-6-sulfonamido)acetamide; D020033:Protein Isoforms; D013449:Sulfonamides; D000469:Alkaline Phosphatase
keywords: Alkaline phosphatase; Enzymes; Inflammatory bowel disease; Inhibitors; Intestinal alkaline phosphatase