Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs

ChemMedChem. 2017 Sep 21;12(18):1542-1554. doi: 10.1002/cmdc.201700340. Epub 2017 Aug 31.


Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.

Keywords: click chemistry; inflammation; nitrogen heterocycles; phosphoinositide 3-kinases; prodrugs.

MeSH terms

  • Animals
  • Binding Sites
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / metabolism
  • Carboxylic Acids / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Mice
  • Microsomes / metabolism
  • Molecular Dynamics Simulation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prodrugs / chemistry*
  • Prodrugs / metabolism
  • Prodrugs / pharmacology
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Quinolones / chemistry
  • Quinolones / metabolism
  • Quinolones / pharmacology
  • Structure-Activity Relationship


  • Carboxylic Acids
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Prodrugs
  • Protein Isoforms
  • Quinolones