Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors

Eur J Med Chem. 2011 Apr;46(4):1404-14. doi: 10.1016/j.ejmech.2011.01.020. Epub 2011 Jan 21.


Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Artificial Intelligence
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • K562 Cells
  • Models, Molecular
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Conformation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / chemistry
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship
  • User-Computer Interface


  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Proto-Oncogene Proteins c-abl
  • pyrrolidine