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

Anna C Giddens; Swarna A Gamage; Jackie D Kendall; Woo-Jeong Lee; Bruce C Baguley; Christina M Buchanan; Stephen M F Jamieson; James M J Dickson; Peter R Shepherd; William A Denny; Gordon W Rewcastle

doi:10.1016/j.bmc.2019.02.050

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. Epub 2019 Feb 25.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Female
Humans
Inhibitory Concentration 50
Mice
Neoplasms / drug therapy
Phosphatidylinositol 3-Kinases / chemistry*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis*
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Phosphoinositide-3 Kinase Inhibitors / therapeutic use
Protein Subunits / antagonists & inhibitors
Protein Subunits / metabolism
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacology
Sulfonamides / therapeutic use
Transplantation, Heterologous
Triazines / chemistry*

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Subunits
Sulfonamides
Triazines
ZSTK474