Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5687-93. doi: 10.1016/j.bmcl.2015.10.098. Epub 2015 Oct 31.

Abstract

Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic cancer. Here, we describe the evolution of our previous PIM1 inhibitor 1 into PIM3 inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic cancer agents.

Keywords: Anti-cancer agent; Drug design; Kinase inhibitor; PIM3; Pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Cell Line, Tumor
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Molecular Dynamics Simulation
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • PIM3 protein, human
  • Protein Serine-Threonine Kinases