title: Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1.
abstract: We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086.
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Bravo
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Teriete
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Raveendra-Panickar
authors.initials: RP
authors.lastname: Dhanya
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Pooi San
authors.initials: PS
authors.lastname: Lee
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Kiffer-Moreira
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Santhi Reddy
authors.initials: SR
authors.lastname: Ganji
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Farquharson
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ncosford@sanfordburnham.org.
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; C000595933:ML086 compound; D054852:Small Molecule Libraries; C497128:PHOSPHO1 protein, human; D010744:Phosphoric Monoester Hydrolases
keywords: ML086; PHOSPHO1; Phosphatase; Probe compound; Vascular calcification