Development of first lead structures for phosphoinositide 3-kinase-C2γ inhibitors

J Med Chem. 2015 Jan 8;58(1):212-21. doi: 10.1021/jm5006034. Epub 2014 Jul 14.

Abstract

The importance of complete elucidation of the biological functions of phosphoinositide 3-kinases (PI3K) was realized years ago. They generate 3-phosphoinositides, which are known to function as important second messengers in many inter- and intracellular signaling pathways. However, the functional role of class II PI3Ks is still unclear. Herein, we describe the synthesis of a panel of compounds that were tested against all eight mammalian PI3K-isoforms. We found inhibitors with some selectivity for class II PI3K-C2γ and also compounds with preferred inhibition of class II PI3K-C2β, providing structural leads to develop selective tool compounds.

MeSH terms

  • Animals
  • Benzenesulfonamides
  • Class II Phosphatidylinositol 3-Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Humans
  • Models, Chemical
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • Sulfonamides
  • Class II Phosphatidylinositol 3-Kinases