Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1512-6. doi: 10.1016/j.bmcl.2009.01.005. Epub 2009 Jan 9.


Pim1 belongs to a family of serine/threonine kinases, which is involved in the control of cell growth, differentiation, and apoptosis. Pim1 plays a pivotal role in cytokine signaling and is implicated in the development of a large number of tumors, representing a very attractive target for anticancer therapy. In this work, we applied a virtual screening protocol aimed at identifying small molecules able to inhibit Pim1 activity. The search of novel inhibitors was performed through a structure-based molecular modeling approach, taking advantage of the availability of the three-dimensional crystal structure of inhibitors bound to Pim1. Starting from the knowledge of protein-ligand complexes, the software LigandScout was used to generate pharmacophoric models, in turn used as queries to perform a virtual screening of databases, followed by docking experiments. As a result, a restricted set of candidates for biological testing was identified. Finally, among the six compounds selected as potential inhibitors of Pim1, two candidates endowed with a significant activity against Pim1 emerged. Interestingly, one of these compounds has a chemical scaffold different from inhibitors previously identified.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Enzyme Activation / drug effects
  • Humans
  • Ligands
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / chemistry*
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • Staurosporine / analogs & derivatives*
  • Staurosporine / metabolism
  • Staurosporine / pharmacology*
  • Structure-Activity Relationship


  • Ligands
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • Staurosporine