Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases

J Med Chem. 2009 Jan 8;52(1):74-86. doi: 10.1021/jm800937p.


The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (4a) was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells. Although 4a is a competitive inhibitor with respect to ATP, a screen of approximately 50 diverse protein kinases demonstrated that it has high selectivity for Pim kinases. Computational docking of 4a to Pim-1 provided a model for lead optimization, and a series of substituted thiazolidine-2,4-dione congeners was synthesized. The most potent new compounds exhibited IC(50)s of 13 nM for Pim-1 and 2.3 microM for Pim-2. Additional compounds in the series demonstrated selectivities of more than 2500-fold and 400-fold for Pim-1 or Pim-2, respectively, while other congeners were essentially equally potent toward the two isozymes. Overall, these compounds are new Pim kinase inhibitors that may provide leads to novel anticancer agents.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use
  • Cell Line
  • Cell-Free System
  • Combinatorial Chemistry Techniques
  • Female
  • Humans
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Neoplasm Transplantation
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis*
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Thiazolidinediones
  • 2,4-thiazolidinedione
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim