Design,synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1 |
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| Affiliation: | 1. 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;2. Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;3. Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;4. The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK;1. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA;2. Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA;3. Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA;4. Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA;1. Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy;2. Department of Experimental Medicine, Section of Biochemistry, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy;3. Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy;4. IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy;5. Debiopharm International S.A., Chemin Messidor 5-7, 1002 Lausanne, Switzerland;6. Roche Diagnostics International AG, Forrenstrasse 2, 6343 Rotkreuz, Switzerland;7. CEBR, University of Genova, V.le Benedetto XV, 7, 16132 Genoa, Italy;8. Cellestia Biotech AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland;9. Innovamol Srls, Viale A. Corassori 24, 41124 Modena, Italy;1. Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA;2. Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA;3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Ave., Madison, WI 53705-2222, USA |
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| 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. |
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| Keywords: | Phosphatase Vascular calcification Probe compound ML086 PHOSPHO1 |
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