2. Academic Validation
  3. Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4308-11. doi: 10.1016/j.bmcl.2014.07.013.
Yalda Bravo 1,  Peter Teriete 1,  Raveendra-Panickar Dhanya 1,  Russell Dahl 1,  Pooi San Lee 1,  Tina Kiffer-Moreira 2,  Santhi Reddy Ganji 1,  Eduard Sergienko 3,  Layton H Smith 3,  Colin Farquharson 4,  José Luis Millán 2,  Nicholas D P Cosford 5
Affiliations

Affiliations

  • 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; Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2 Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 3 Conrad Prebys Center for Chemical Genomics, 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.
  • 5 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.
PMID: 25124115 DOI: 10.1016/j.bmcl.2014.07.013
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.

Keywords

ML086; PHOSPHO1; Phosphatase; Probe compound; Vascular calcification.

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