2. Academic Validation
  3. Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

  • Bioorg Med Chem. 2019 Apr 15;27(8):1529-1545. doi: 10.1016/j.bmc.2019.02.050.
Anna C Giddens 1,  Swarna A Gamage 1,  Jackie D Kendall 2,  Woo-Jeong Lee 3,  Bruce C Baguley 2,  Christina M Buchanan 4,  Stephen M F Jamieson 2,  James M J Dickson 5,  Peter R Shepherd 6,  William A Denny 2,  Gordon W Rewcastle 7
Affiliations

Affiliations

  • 1 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 2 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 3 Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 4 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 5 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; School of Biological Sciences, Faculty of Science, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 6 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 7 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: g.rewcastle@auckland.ac.nz.
PMID: 30850264 DOI: 10.1016/j.bmc.2019.02.050
Abstract

Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα Enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.

Keywords

PI3K; Phosphatidylinositol 3-kinase; SN32976; ZSTK474; p110α.

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