Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound

J Med Chem. 2012 Jun 14;55(11):5151-64. doi: 10.1021/jm3001289. Epub 2012 May 17.


Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Databases, Factual
  • Drug Screening Assays, Antitumor
  • G1 Phase / drug effects
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Leukemia
  • Models, Molecular
  • Molecular Structure
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Aza Compounds
  • Benzofurans
  • Indoles
  • Proto-Oncogene Proteins c-pim-1

Associated data

  • PDB/3UMW
  • PDB/3UMX