Discovery of N-substituted 7-azaindoles as Pan-PIM kinases inhibitors - Lead optimization - Part III

Bioorg Med Chem Lett. 2019 Feb 1;29(3):491-495. doi: 10.1016/j.bmcl.2018.12.015. Epub 2018 Dec 10.

Abstract

N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.

Keywords: AML; Cancer; Lead; PK/PD; Pan-PIM kinases; Tumor growth inhibition.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Mice
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • 7-azaindole dimer
  • Antineoplastic Agents
  • Indoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim