Structure-based design of low-nanomolar PIM kinase inhibitors

Bioorg Med Chem Lett. 2015 Feb 1;25(3):474-80. doi: 10.1016/j.bmcl.2014.12.041. Epub 2014 Dec 19.

Abstract

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.

Keywords: De novo design; Kinase inhibitors; PIM; PIM inhibitors; Rational design.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Hydrogen Bonding
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim